Tunable, controlled-release, urethane-containing elastomers and processes of forming the same

ABSTRACT

A process forms an implantable product including poly(glycerol sebacate) urethane (PGSU) loaded with an active pharmaceutical ingredient (API). The process includes homogeneously mixing a flowable poly(glycerol sebacate) (PGS) resin with the API and a catalyst to form a resin blend. The process also includes homogeneously combining the resin blend with an isocyanate to form a reaction mixture and injecting the reaction mixture to form the PGSU loaded with the API. An implantable product includes a PGSU loaded with an API. In some embodiments, the implantable product includes at least 40% w/w of the API, and the implantable product releases the API by surface degradation of the PGSU at a predetermined release rate for at least three months under physiological conditions. In some embodiments, the PGSU is formed from a PGS reacted with an isocyanate at an isocyanate-to-hydroxyl stoichiometric (crosslinking) ratio in the range of 1:0.25 to 1:1.25.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to and the benefit of U.S. ProvisionalApplication No. 62/720,412 filed Aug. 21, 2018 and U.S. ProvisionalApplication No. 62/872,793 filed Jul. 11, 2019, which are herebyincorporated by reference in their entirety.

FIELD OF THE INVENTION

This application is directed to processes of forming urethane-containingpolymers and polymers formed by such processes. More specifically, thisapplication is directed to processes of forming poly(glycerol sebacate)urethane polymers with tunable controlled release rates and polymersformed by such processes.

BACKGROUND OF THE INVENTION

The majority of biodegradable biomaterial polymers used for drugdelivery are bulk eroders that exhibit a dose-dependent activepharmaceutical ingredient (API) release rate, where increasing the drugloading concentration increases the relative release rate. With suchpolymers, achieving high drug loadings that also sustain release forgreater than 3 months is challenging, because the increased loading alsogenerates a steeper concentration gradient between the polymer matrixand the surrounding environment. That, in turn, drives release to occurfaster. Hence, for bulk eroders such as poly(lactic-co-glycolic acid)(PLGA), polyglycolic acid (PGA), polylactic acid (PLA), polycaprolactone(PCL), and others, the release rate is often sufficiently low to achievegreater than three months of controlled release therapy when the loadingis about 40% w/w or less, but loadings of about 50% w/w or greater oftenexhibit significantly faster release rates and thus often only provideat most one month of controlled release therapy.

This same limitation occurs with non-degradable polymers, such aspoly(ethylene-co-vinyl acetate) (EVA), polyurethane (PU), and silicone,since bulk eroding and non-eroding drug delivery systems are bothdiffusion-driven. This is demonstrated, for example, in Barrett et al.(“Extended Duration MK-8591-Eluting Implant as a Candidate for HIVTreatment and Prevention”, Antimicrob. Agents Chemother., Vol. 62, Issue10, 2018), where EVA, PCL, and PLA show a steep increase in release rateas the drug loading increases from 40% w/w, to 50% w/w, to 60% w/w, andto 80% w/w. At 60% w/w loading, release from all three polymers is only2 months in duration. At 80% w/w, release duration drops to 1 month induration. Moreover, bulk eroding polymers often demonstrate dose dumpingonce a critical mass loss has been reached.

While release rate is highly dependent on the solubility of the API, itwould be highly advantageous to have a polymer carrier that is capableof delivering APIs across a solubility spectrum in a sustained manner,for at least three months and potentially many months longer. Highlysoluble APIs pose a challenge to non-degradable and bulk erodingpolymers, since Biopharmaceutical Classification System (BCS) class I(high solubility, high permeability) and class III (high solubility,poor permeability) APIs are likely to rapidly diffuse away from thepolymer matrix, causing a large burst release and fast release rate. Onthe other hand, poorly soluble APIs also pose a challenge tonon-degradable and bulk eroding polymers, since BCS class II (lowsolubility, high permeability) and BCS class IV (low solubility, lowpermeability) APIs have a difficult time diffusing away from the polymermatrix. Sufficient release rates cannot be achieved, especially within areasonable timeframe after implantation. The majority of new drugentities developed by the pharmaceutical industry are BCS class II andIV, and so solubility and permeability concerns are becomingincreasingly important to manage for effective controlled drug delivery.However, BCS class I and III APIs are still very much of interest forcontrolled release as well. Thus having a polymeric delivery system thatcan deliver both highly-soluble and poorly-soluble APIs in the form of amatrix that is essentially agnostic to the API would be desirable.Further, having a polymeric delivery system that does not solely rely ondiffusion, but instead releases the API through surface erosion, eitherin combination with diffusion or by surface erosion alone, is alsohighly desirable.

A conventional method of producing PGSU polymeric films issolvent-based, using a 10% w/v PGS solution in dimethylformamide (DMF)heated to 55° C. (131° F.) in the presence of catalyst, addinghexamethylene diisocyanate (HDI) dropwise, and allowing to react for 5hours prior to casting into molds for solvent evaporation (see, forexample, U.S. Patent Application Publication No. 2013/0231412, which ishereby incorporated by reference in its entirety). Such conventionalmethods may reduce the reaction time and/or temperature by inclusion ofa catalyst, such as, for example, stannous octoate, triethylene diamine,bis(dimethylaminoethyl)ether, dimethylethanolamine, dibutyltindilaurate, or a bismuth-based catalyst. The temperature, the solvent,the dropwise isocyanate addition, and the reaction time limitations ofthis conventional approach are not amenable to API incorporation or highthroughput manufacture of an API-loaded product.

A conventional method of producing PGSU polymeric films is solvent-free,using 100% w/v PGS resin, mixing with a pre-mixture of HDI and catalyst,and spin coating onto modified glass coverslips for 3000 rpm for 3minutes (see, for example, U.S. Patent Application Publication No.2013/0231412). Such conventional methods may reduce the reaction timeand/or temperature by inclusion of a catalyst, such as, for example,stannous octoate, triethylene diamine, bis(dimethylaminoethyl)ether,dimethylethanolamine, dibutyltin dilaurate, or a bismuth-based catalyst.The unspecified mixing technique and the spin coating limitations ofthis conventional approach are not amenable to uniform HDI mixing, largevolume HDI incorporation, API incorporation, or high throughputmanufacture of an API-loaded product. Additionally, the pre-mixture ofisocyanate and catalyst may cause isocyanate self-condensation andsubsequent dimerization, trimerization, and/or formation of otherisocyanate self-reaction products, which may reduce the efficiency ofthe isocyanate-polyol reaction and result in lower crosslinking thandesired. The pre-mixture of isocyanate and catalyst may also introducemoisture that the isocyanate will readily and preferentially react with,causing formation of carbamic acid and amine, and in turn causingformation of urea.

What is needed is a process that avoids the use of high temperaturesnormally required for PGS crosslinking into a thermoset product, aprocess that permits higher loadings of at least 10% w/w up to 90% w/wAPI with controlled release of the API for at least three months, aprocess that incorporates isocyanate volumes equivalent toisocyanate-to-hydroxyl (NCO:OH) stoichiometric ratios between 1:0.25 and1:1.25, a process that avoids the use of solvents for API loading, aprocess that handles the high viscosity of solvent-less PGS and high APIloadings, a process that handles the disparate viscosities ofsolvent-less API-loaded PGS and isocyanate, a process that prevents airbubble formation, air entrainment, and air entrapment during urethanereaction, a process that uniformly and precisely incorporates anddistributes PGS, isocyanate, catalyst, and API into a homogeneous blend,a process that can form the homogeneous blend within the working time ofthe PGSU reaction without compromising uniformity or precision, and/oran elastomer loaded with up to 90% w/w API that provides controlledrelease of the API for at least three months.

BRIEF DESCRIPTION OF THE INVENTION

Exemplary embodiments are directed to processes that form poly(glycerolsebacate) urethane (PGSU) having a degradation rate and correspondingAPI release kinetics that are both tunable by selection of the startingPGS polyol structure and the process conditions to form the API-loadedPGSU.

Exemplary embodiments are directed to PGSU formulations that incorporatehigh API loading and provide sustained API release, independent ofloading concentration, to maintain therapeutic levels over the course ofmany months.

Exemplary embodiments are directed to manufacturing methods for PGSUthat eliminate any use of high temperature or solvent, therebypermitting incorporation of thermolabile and form-sensitive APIs intothe PGSU.

According to an exemplary embodiment, a process forms an implantableproduct comprising poly(glycerol sebacate) urethane loaded with anactive pharmaceutical ingredient. The process includes homogeneouslymixing a flowable poly(glycerol sebacate) resin with the activepharmaceutical ingredient and a catalyst to form a resin blend. Theprocess also includes selecting an amount of isocyanate such that anisocyanate-to-hydroxyl stoichiometric ratio is in the range of 1:0.25 to1:1.25. The process further includes homogeneously combining the resinblend with the isocyanate to form a reaction mixture and injecting thereaction mixture to form the poly(glycerol sebacate) urethane loadedwith the active pharmaceutical ingredient.

According to another exemplary embodiment, an implantable productincludes a poly(glycerol sebacate) urethane loaded with an activepharmaceutical ingredient. The implantable product releases the activepharmaceutical ingredient by surface degradation of the poly(glycerolsebacate) urethane at a predetermined release rate for at least threemonths under physiological conditions.

According to yet another exemplary embodiment, an implantable productincludes a poly(glycerol sebacate) urethane loaded with an activepharmaceutical ingredient. The poly(glycerol sebacate) urethane isformed from a poly(glycerol sebacate) reacted with an isocyanate at anisocyanate-to-hydroxyl stoichiometric ratio is in the range of 1:0.25 to1:1.25.

Various features and advantages of the present invention will beapparent from the following more detailed description, taken inconjunction with the accompanying drawings which illustrate, by way ofexample, the principles of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows viscosity as a function of reaction time for awater-mediated PGS polymerization process and a non-water-mediated PGSpolymerization process.

FIG. 2 shows Fourier-transform infrared (FTIR) spectra for a variety ofPGS resin types.

FIG. 3 shows GPC spectra for high-molecular-weight PGS resins formed byeither a water-mediated process or a non-water-mediated process.

FIG. 4 shows PGSU crosslinking level as a PGS:HDI mass ratio based onFTIR spectra and a multiple linear regression model for PGSU made from avariety of PGS resin types.

FIG. 5 shows PGSU crosslinking density as determined by Flory-Rehnerswell testing for PGSU made from a variety of PGS resin types.

FIG. 6 shows elastic modulus for PGSU films made from a variety of PGSresin types.

FIG. 7 shows strain at break for PGSU made from a variety of PGS resintypes.

FIG. 8 shows weight-average molecular weight and polydispersity index ofextractables collected from PGSU films from a variety of PGS resintypes.

FIG. 9 shows mass and mass percentage of extractables collected fromPGSU films, made from a variety of PGS resin types, based on the mass ofthe PGSU film.

FIG. 10 shows bulk images of 60% w/w caffeine-loaded PGSU films afterwater exposure for different PGS resin molecular weights and differentPGS:HDI ratios for PGSU films from a variety of PGS resin types.

FIG. 11 shows cross-sectional scanning electron microscopy (SEM) imagesof 60% w/w caffeine-loaded PGSU films after water exposure for differentPGS resin molecular weights and different PGS:HDI mass ratios for PGSUfilms from a variety of PGS resin types.

FIG. 12 shows how PGSU crosslinking density, as determined by anempirical swell test, relates to PGS:HDI mass ratio when usingRegenerez® PGS resin (Secant Medical, Inc., Perkasie, Pa.).

FIG. 13 shows how PGSU crosslinking density, as described byisocyanate-to-hydroxyl stoichiometric ratio, relates to PGS:HDI massratio when using Regenerez® PGS resin.

FIG. 14 shows swellability in water of unloaded PGSU films having a massratio of 3.6:1 PGS:HDI in a saline solution at 23° C. and 37° C., asmeasured by % weight change across 14 days, for PGSU made fromRegenerez® PGS resin.

FIG. 15 shows thermoset PGSU products eight months after manufacture,for PGSU made from Regenerez® PGS resin.

FIG. 16 shows non-cumulative release curves as plasma concentration ofAPI release in vivo for implantable PGSU rod products with 15% to 25%w/w API loadings at different crosslinking densities, for PGSU made fromRegenerez® PGS resin.

FIG. 17 shows cumulative release curves as percent of API released invitro for implantable PGSU rod products with 15% to 25% w/w API loadingsat different crosslinking densities, for PGSU made from Regenerez® PGSresin.

FIG. 18 shows in vitro-in vivo overlays for cumulative release forimplantable PGSU rod products with 15% to 25% w/w API loadings atdifferent crosslinking densities, for PGSU made from Regenerez® PGSresin.

FIG. 19 shows in vitro-in vivo correlations for cumulative release forimplantable PGSU rod products with 15% to 25% w/w API loadings atdifferent crosslinking densities, for PGSU made from Regenerez® PGSresin.

FIG. 20 shows the observed near zero-order release rate constantrelative to the initial caffeine loading for the in vivo and in vitroresults of FIG. 16 and FIG. 17, for PGSU made from Regenerez® PGS resin.

FIG. 21A shows cross-sectional images of caffeine-loaded PGSU rodsbefore and after implantation in rats, for PGSU made from Regenerez® PGSresin.

FIG. 21B shows cross-sectional images of caffeine-loaded PGSU rodsbefore and after dissolution testing, for PGSU made from Regenerez® PGSresin.

FIG. 22 shows water permeation and percolation of 40% w/wcaffeine-loaded PGSU films and 60% w/w caffeine-loaded PGSU films, forPGSU made from Regenerez® PGS resin.

FIG. 23 shows FTIR spectra of homogeneously mixed PGSU achieved by highshear mixing, before and after gamma sterilization, for PGSU made fromRegenerez® PGS resin.

FIG. 24 shows FTIR spectra of poorly mixed PGSU resulting from low shearmixing, for PGSU made from Regenerez® PGS resin.

FIG. 25 shows histology at the three month timepoint of explanted PGSUrod products, initially with and without 15% to 25% w/w API loading, andthe surrounding subcutaneous tissue and underlying muscle, forbiocompatibility assessment, for PGSU made from Regenerez® PGS resin.

FIG. 26 shows the mechanical testing results from 3-point bending ofPGSU rod products with and without 10% to 30% w/w API loading, for PGSUmade from Regenerez® PGS resin.

FIG. 27 shows the mechanical testing results from axial compressionapplied to PGSU rod products with and without 10% to 30% w/w APIloading, for PGSU made from Regenerez® PGS resin.

FIG. 28 shows the mechanical testing results from axial tension appliedto PGSU sheets without API loading, for PGSU made from Regenerez® PGSresin.

FIG. 29A shows the cross-section of 40% w/w caffeine-loaded PGSU rodproducts fabricated by a solvent-less, dual-barrel syringe process thatinvolves high shear mixing and extrusion into molds, for PGSU made fromRegenerez® PGS resin.

FIG. 29B shows the cross-section of 60% w/w caffeine-loaded PGSU rodproducts fabricated by a solvent-less, dual-barrel syringe process thatinvolves high shear mixing and extrusion into molds, for PGSU made fromRegenerez® PGS resin.

FIG. 30 shows crosslink density, loading, and elastic modulus of the 40%w/w caffeine-loaded PGSU rod product of FIG. 29A.

FIG. 31 shows crosslink density, loading, and elastic modulus of the 60%w/w caffeine-loaded PGSU rod product of FIG. 29B.

Wherever possible, the same reference numbers will be used throughoutthe drawings to represent the same parts.

DETAILED DESCRIPTION OF THE INVENTION

Provided herein are compositions and processes of forming compositionsincluding poly(glycerol sebacate) urethane (PGSU) polymers with tunablecontrolled release rates for release of a loaded active pharmaceuticalagent (API).

Poly(glycerol sebacate) (PGS) is a cross-linkable elastomer formed as aco-polymer from glycerol and sebacic acid. PGS is biocompatible andbiodegradable, reduces inflammation, improves healing, and hasantimicrobial properties, all of which make it useful as a biomaterialin the biomedical field.

PGS has limited processability options as a result of the constraints onadvancing polycondensation reactions at low temperatures in the presenceof an API or active biologic.

Bioresorbable elastomeric urethanes have been developed as a source ofengineering material that provides both an elastomeric engineeringcompliance property to mimic the viscoelastic properties of tissue and abiodegradability property that may be tuned to degrade or deliver in acontrolled surface-eroding mechanism, unlike the plastic and rigidlactides and glycolides that bulk degrade and lack sufficientviscoelasticity. Such a surface mechanism makes the polyester polyol,PGS, and its urethane derivative, poly(glycerol sebacate) urethane(PGSU), excellent candidates for controlled drug release. The mechanismof surface erosion for PGS and PGSU is hydrolysis, enzymaticdegradation, and oxidative degradation.

As a surface eroder that at least initially shows water impermeability,API-loaded PGSU does not experience a concentration gradient between theinternal polymer and external environment, and the release rate isdictated by the rate of surface erosion. Accordingly, PGSU offers anearly dose-independent API release, where higher drug loading does notdramatically impact the rate of release. PGSU has been shown to maintaina near-constant release rate from 10% w/w to 90% w/w API loadings.Additionally, PGSU has been shown to maintain near zero order releasekinetics across 10% w/w to 90% w/w loadings.

PGSU without API loading only swells about 2% w/w over two weeks insaline solution at both 23° C. and 37° C., indicating the low waterpermeability and hydrophobicity of PGSU as a base material. UnloadedPGSU films with a thickness of 1 mm show no water permeation orpercolation over four weeks at 37° C. API-loaded PGSU films with athickness of 1 mm do experience water permeation and percolation overfour weeks at 37° C., but this behavior is dependent on the drugdistribution, drug particle size, drug loading, and crosslinking densityof the PGSU matrix. If large agglomerations of API are embedded in thePGSU matrix, water or fluids may percolate in, following interconnectedchannels formed by API particles that are adjacent or touching. Oncewater percolates in, the water may solubilize and carry away API viadiffusion. This can be prevented with thorough mixing of PGSU and theAPI, potentially by also applying high shear or using grinding mediaduring mixing, to break up agglomerations and/or prevent agglomerationformation. High API loading is another instance where percolation mayoccur, since the API particles are packed closer together within thematrix. In this case, the homogeneous distribution of API and a smallAPI particle size are critical to preventing interconnected ingresschannels from forming. Beyond percolation, water can also permeate intoand out of the drug-loaded PGSU matrix. As evidenced by unloaded PGSUfilms swelling about 2% w/w as mentioned above, this slight amount ofliquid transport is enough for water to infiltrate in and help the APIdiffuse out, but it is dependent on the PGSU wall thickness. Thisexplains why unloaded PGSU films swell slightly but do not demonstratewater penetration through a thickness of 1 mm.

Drug-loaded PGSU films contain much thinner walls of PGSU surroundingAPI particles, so 2% w/w swelling could allow water to penetrate betweenregions of API particles. This can be mitigated by increasing thecrosslinking density of PGSU, to both slow down the permeation of waterthrough PGSU and also slow down the degradation rate of the thin wallsseparating API particles. It has been demonstrated that a lowercrosslinked PGSU with high drug loading exhibits water percolation andpermeation until the water carries the drug through the full 1-mm filmthickness. This diffusion is a slow seepage, to the point where thediffused water evaporates on the other side of the film, leaving behindthe drug to re-crystallize on the film's back side. In contrast, ahigher crosslinked PGSU with the same high drug loading avoids theseissues by inhibiting permeation. Higher crosslinked PGSU means a smallermesh size, which limits permeation. If the mesh size of the polymer istight enough, small molecules like APIs or even solvents cannot passthrough. Percolation and permeation can be related to burst release anddiffusion in practice. Reducing percolation and permeation results inreduced burst release and diffusion, so that drug delivery occurs solelyby surface erosion and so that diffusion effects are secondary ornon-existent.

Urethane chemistry, including that which forms PGSU, is driven bycatalytic action. Without precise characterization of the startingpolyol, the urethane chemistry to form PGSU does not achieve a reliableurethane-containing elastomer product with predictable crosslinking,degradation rate, and subsequent release kinetics for drug deliveryapplications. PGS otherwise offers many potential advantages as astarting polyol, namely that it is a surface-eroding elastomer thatelicits minimal inflammatory response and degrades into byproducts thatare readily metabolized by cells. The high temperatures required tocrosslink and thermoset PGS, however, are often a deterrent for APIincorporation into a PGS drug delivery device, since many APIs havethermolabile properties.

During API compounding, solvent-free processing eliminates the time andcost associated with drying steps, which may often require an increasein temperature that incurs additional cost. Solvent exposure may alsohave a detrimental effect on the physical form of the API, causingstructural variations that may affect API stability, performance, andefficacy. Heat exposure may similarly have a detrimental effect on APIphysiochemical characteristics. The absorption, distribution,metabolism, and excretion (ADME) characteristics of an API are typicallythoroughly optimized during primary formulation in drug discovery, andany changes to crystallinity, amorphism, polymorphism, salt form, freebase form, or free acid form that occur during secondary formulation areundesirable and to be avoided, often at great lengths.

In exemplary embodiments, a manufacturing process reduces or eliminatesthe use of solvent and heat, thereby creating a manufacturingenvironment that is suitable for inclusion of thermolabile andform-sensitive APIs, while maintaining rheological properties and aworking time suitable for homogeneous mixing followed by rapid partmolding. In exemplary embodiments, the manufacturing process is free ofsolvents and applied heat.

In exemplary embodiments, a manufacturing process is scalable and/orcontinuous, and reduces or eliminates moisture during homogeneous mixingsuitable for high viscosity, disparate viscosity, equivalent volumes,and/or disparate volumes of immiscible components.

In exemplary embodiments, the implantable product is a surface-eroding,flexible PGSU cylindrical rod, formed by reaction injection molding withup to 90% w/w API loading, no solvent use, and no heat exposure above60° C., that is implantable subcutaneously and sustains zero order orfirst order release kinetics for up to at least six months.

In exemplary embodiments, the implantable product is formed, in part,from a chemically-characterized poly(glycerol sebacate) (PGS) resin andan isocyanate selected, in part, based on the chemical characterizationof the PGS resin. Appropriate isocyanates may be aliphatic or aromaticin structure. Appropriate isocyanates may include, but are not limitedto, hexamethylene diisocyanate (HDI), methylene diphenyl diisocyanate(MDI), toluene diisocyanate (TDI), isophorone diisocyanate (IPDI),methylenebis(cyclohexyl isocyanate) (HMDI), tetramethylxylenediisocyanate (TMXDI), aliphatic isocyanates, aromatic isocyanates,aliphatic-aromatic combination isocyanates, and/or blocked isocyanates.Some isocyanates may be slower reacting based on their aliphatic,aromatic, or aliphatic-aromatic combination structure. The speed ofreaction may be tuned based on the needs of the manufacturing process ofinterest.

In some embodiments, the chemically-characterized PGS resin is preparedvia a water-mediated polycondensation reaction. Thechemically-characterized PGS resin may include a molecular weight above10,000 Da, alternatively above 15,000 Da, alternatively above 25,000 Da,or any value therebetween. The chemically-characterized PGS resin mayinclude a polydispersity index less than 16, alternatively less than 14,alternatively less than 12, alternatively less than 10, alternativelyless than 8, or any value, range, or sub-range therebetween. Thechemically-characterized PGS resin may include an acid number between 20and 80, alternatively between 30 and 70, alternatively between 40 and60, alternatively between 35 and 55, alternatively between 40 and 50, orany value, range, or sub-range therebetween. Thechemically-characterized PGS resin may include a hydroxyl number between160 and 240, alternatively between 180 and 220, alternatively between190 and 210, or any value, range, or sub-range therebetween. As usedherein, a “hydroxyl number” value is as determined by American Societyfor Testing and Materials (ASTM) E222. The chemically-characterized PGSresin may include a stoichiometric ratio of glycerol-sebacic acidbetween 1:0.25 and 1:2, alternatively between 1:0.5 and 1:1.5,alternatively between 1:0.75 and 1:1.25, or any value, range, orsub-range therebetween. The PGSU may be formulated with a stoichiometricratio of isocyanate-to-hydroxyl between 1:0.25 and 1:2, alternativelybetween 1:0.25 and 1:1.5, alternatively between 1:0.25 and 1:1.25, orany value, range, or sub-range therebetween. One or more of theseparameters may be controlled to tailor the PGSU degradation rate toachieve desired API release kinetics.

In some embodiments, the water-mediated process to form PGS or a similarelastomer follows a procedure disclosed in U.S. Patent ApplicationPublication No. 2015/0344618, which is hereby incorporated by referencein its entirety. It may be desirable to charge the glycerol and water toa vessel in a stoichiometric ratio, water-to-glycerol, of about 1:1 orgreater, alternatively about 1:1 to about 4:1, alternatively about 2:1to about 4:1, alternatively about 2:1 or greater, alternatively about3:1, or any value, range, or sub-range therebetween. After the glycerolhas dissolved in the vessel, sebacic acid is added to the vessel in apredetermined stoichiometric ratio, glycerol-to-sebacic acid, of about1:0.9 to about 1:2.5, alternatively about 1:1, or any value, range, orsub-range therebetween.

The mixture is then heated to a temperature of about 50° C. to about200° C. (122° F. to 392° F.), preferably to a temperature of about 140°C. (284° F.) or greater in order to melt the sebacic acid. The mixtureis heated for about 1 hour or more and may be stirred while heating. Thevessel may be under an inert gas, such as nitrogen or argon, or under avacuum while it is being heated. After the mixture is heated, it isstirred at an elevated temperature to distribute the contents of themixture. The stirring step may last up to 1 hour or more. The vessel maybe kept under an inert atmosphere while the mixture is being mixed tohomogeneity. After the mixture is dispersed, the water is removed bydistillation.

In some embodiments, the vessel is heated under nitrogen to about 160°C. (320° F.) for about 1 hour. After the mixture is heated, the mixtureis stirred at about 130° C. (266° F.), under nitrogen for about 1 hourto thoroughly disperse the sebacic acid until the mixture ishomogeneous. The reaction vessel is then purged with nitrogen for about24 hours at about 120° C. (248° F.). After the system has been purged, avacuum of about 10 Torr is applied to the vessel while maintaining atemperature of about 120° C. (248° F.) or higher for about 26 hours.

Distillation may be achieved by heating the mixture, or by putting thevessel under a vacuum, or both. The temperature of the vessel may beabout 100 to 200° C. (212 to 392° F.) or preferably about 130 to 150° C.(266 to 302° F.). The pressure of the vessel may be about 760 Torr orlower. In exemplary embodiments, the pressure is 20 Torr or less. Thedistillation is continued until the polymer reaches a desired averagemolecular weight, or until no more water is distilled. The removal ofwater from the vessel allows the monomers to react, thus the polymer hasbeen synthesized by the end of the distillation.

The PGS resin molecular weight, polydispersity index, reaction process,degree of branching, acid number, hydroxyl number, andglycerol-to-sebacic acid stoichiometric ratio all may impact how PGSU iscrosslinked and accordingly how PGSU is degraded. Conventional processesdo not address any of these parameters for PGSU other than the molecularweight, which is typically restricted to be between 3,000 Da and 25,000Da. Molecular weights about 25,000 Da or greater offer a slower APIrelease rate that is more suitable for sustained release applications,such as long-acting implantables. It will be appreciated by one ofordinary skill in the art that these parameters may be tailored tofine-tune the API release rate from the biodegradable implantableproduct. A tight control of these specific parameters to achieve animplantable product with reliable and tunable drug release has not beenpreviously identified. Conventional processes for synthesizing PGS resinwithout water-mediation during the polycondensation reaction result in aPGS resin with higher polydispersity index for molecular weights greaterthan 25,000 Da, compared to PGS resin synthesized using water-mediatedpolycondensation. Conventional processes for synthesizing PGS resinwithout water-mediation also result in different PGSU crosslinkingorganization and three-dimensional crosslinking structure than PGS resinsynthesized using water-mediated polycondensation, as evidenced by waterpermeation and percolation testing, even though Flory-Rehner swellingand tensile testing on the bulk material shows a similar crosslinkingdensity and elastic modulus, respectively, and Fourier-transforminfrared (FTIR) spectroscopy on the PGS resin material shows similarchemical functionality. Conventional processes for synthesizing PGSresin without water-mediation also result in different amounts anddifferent proportions of extractables than PGS resin synthesized usingwater-mediated polycondensation. Excess extractables may react withisocyanate, quenching it, resulting in an unintentionally lowercrosslinking than expected and/or desired.

In some embodiments, the active pharmaceutical ingredient isincorporated by blending neat API powder with PGS polyol resin prior tourethane reaction. Solvent extraction methods demonstrated no observablecross-reaction of active pharmaceutical ingredient into the polymernetwork during urethane crosslinking, nor are any detrimental orcross-reaction effects observed after gamma sterilization. Thetwo-component PGSU reaction should be thoroughly mixed within its potlife to achieve API content uniformity and crosslinking uniformity.

Selection of an appropriate isocyanate-to-hydroxyl stoichiometric ratioprovides a stable implantable product with optical clarity that does notexhibit clouding, hazing, blooming, or stiffening over time upon storageat room temperature and room humidity ambient conditions. When theisocyanate-to-hydroxyl stoichiometric ratio is less than 1:2, such as,for example, 1:3 or 1:4, the implantable product suffers from cloudingand stiffening when stored at ambient conditions, which is detrimentalto product shelf life and reflects an unstable product.

Selection of an appropriate isocyanate-to-hydroxyl stoichiometric ratioprovides a highly crosslinked implantable product with properties forsustained, surface erosion-mediated drug release for long durations andhigh drug loadings, namely reduced water percolation and permeation,reduced API burst release and diffusion, and slower PGSU degradation.

Exemplary embodiments formulate PGSU specifically for manufacturingprocesses, such as molding, particularly without the use of any solventor heat above 40° C. while still maintaining homogeneous mixing andincorporation of API and isocyanate.

An implantable API-loaded PGSU product may include a PGSU article ofmanufacture in the form of a monolithic rod, a tube, a film, a sheet, amulti-layered composite, a coating, a fiber, a textile, a porousscaffold, microparticles, and/or nanoparticles. The monolithic rod mayhave a circular, elliptical, square, or rectangular cross section. Themonolithic rod may contain multiple layers or compartments, arrangedconcentrically, axially, longitudinally, or in another pattern.

Starting polyol characteristics may include a highly-branched PGSprepolymer resin as a starting reactant, a PGS resin with a molecularweight greater than 10,000 Da, a PGS resin with a polydispersity indexless than 12, a PGS resin prepared via a water-mediated polycondensationreaction, a PGS resin with an acid number between 30 and 60, a PGS resinwith a hydroxyl number between 160 and 240, a PGS resin with aglycerol-to-sebacic acid stoichiometric ratio between 1:0.5 and 1:1.5,or combinations thereof.

In some embodiments, an implantable API-loaded PGSU product having aloading in the range of 20% to 40% w/w maintains asubstantially-constant release rate in vitro of about 3% per day for aperiod of more than a month, although API loadings outside this rangemay also produce similar desirable release results, such as an APIloading of 18.2 w/w % or less, as shown in FIG. 16 and FIG. 17.

In some embodiments, an implantable API-loaded PGSU product having aloading of about 3.5% w/w and at a relatively low crosslink densitymaintains a substantially-constant release rate in vitro of about 0.06%per day for a period of two months.

Exemplary embodiments can be used to create a PGSU biodegradable polymermatrix capable of high solids loading with minimal solvent and heatexposure, capable of being mixed homogeneously, formed via molding,preferably cast molding or injection molding, having mechanicalproperties sufficient for delivery via a cannula or needle, thatprovides long-term patient comfort, or combinations thereof.

Exemplary embodiments may create implantable API-loaded PGSU productswithout exposure to excessive heat, without exposure to solvents, orcombinations thereof.

Exemplary embodiments remain within ranges for product-criticalparameters that are specific to PGS chemistry that impact PGSU's abilityto be a stable, tunable, and reliable drug delivery vehicle.

Exemplary embodiments create a PGSU biodegradable polymer matrix capableof high API loading while maintaining zero order (controlled), near-zeroorder release characteristics, first-order release characteristics, ornear first-order release characteristics over a time period of at leastthree months.

Exemplary embodiments may have any geometric shape, including, but notlimited to, pyramidal, spherical, cylindrical, or cubic, and may includeany structure, including, but not limited to, a porous structure, afibrous structure, and/or a patterned microstructure.

In some embodiments, the implantable product includes a structure toprovide ascending release kinetics over the course of weeks tocounteract functional tolerance to the API from prolonged exposure. Insome embodiments, the implantable product provides ascending,descending, and/or oscillatory release characteristics over a 24-hourcycle that repeats for the lifetime of the implant, such as to providedelivery results similar to a daily oral push-stick osmotic pump, tocounteract acute tolerance to the API from repeated exposure.

In some embodiments, the implantable product includes multiplematerials, such as, for example, different layers or different zoneshaving different physiochemical properties created by tuning the PGSU,and thus providing different release rates. In some embodiments, theimplantable product includes multiple APIs. In some embodiments, theimplantable product includes multiple polymers.

Exemplary embodiments provide an API-loaded PGSU implant as animplantable product formed from a PGS resin, an isocyanate, and an API.

Any API may be loaded in the implantable PGSU product. Appropriate typesof APIs may include, but are not limited to, therapeutic agents (suchas, for example antibiotics, non-steroidal anti-inflammatory drugs(NSAIDs), glaucoma, macular degeneration, and other ophthalmologicmedications, angiogenesis inhibitors, drugs to treat diabetes, drugs totreat neurodegeneration, and/or neuroprotective agents), cytotoxicagents, diagnostic agents (such as, for example, contrast agents,radionuclides, fluorescent moieties, luminescent moieties, and/ormagnetic moieties), prophylactic agents (such as, for example, vaccines,drugs for human immunodeficiency virus (HIV) prophylaxis and HIVtreatment, contraceptive drugs), pain management agents, addictionmanagement agents (such as, for example, opioids, and/or nicotine),plant or herbal extracts (such as, for example, a cannabinoid, such as,for example, tetrahydrocannabinol) and/or nutraceutical agents (such as,for example, vitamins, caffeine, and/or minerals).

Appropriate API therapeutic agents may include, but are not limited to,small molecules, such as, for example, cytotoxic agents; nucleic acids,such as, for example, small interfering ribonucleic acid (siRNA), RNAinterference (RNAi), and/or microRNA agents; proteins, such as, forexample, growth factors and/or antibodies; peptides; lipids;carbohydrates; hormones; metals; radioactive elements and compounds;drugs; vaccines; and/or immunological agents.

Appropriate API therapeutic agents may additionally or alternativelyinclude, but are not limited to, small molecules with pharmaceuticalactivity, organic compounds with pharmaceutical activity,clinically-used drugs, antibiotics (such as, for example, penicillin),anti-viral agents, anesthetics, anticoagulants, anti-cancer agents,inhibitors of enzymes (such as, for example, clavulanic acid), promotorsof enzymes, steroidal agents, pro-healing agents, pro-polymerdegradation agents, anti-oxidants, anti-inflammatory agents,anti-neoplastic agents, antigens, vaccines, antibodies, decongestants,antihypertensives, sedatives, birth control agents, progestationalagents, anti-cholinergics, analgesics, anti-depressants,anti-psychotics, β-adrenergic blocking agents, diuretics, cardiovascularactive agents, vasoactive agents (such as, for example, epinephrine),anti-glaucoma agents, neuroprotectants, angiogenesis promotors, and/orangiogenesis inhibitors.

Appropriate API antibiotics may include, but are not limited to,β-lactam antibiotics (such as, for example, ampicillin, aziocillin,aztreonam, carbenicillin, cefoperazone, ceftriaxone, cephaloridine,cephalothin, cloxacillin, moxalactam, penicillin G, piperacillin, and/orticarcillin), macrolides, monobactams, rifamycins, tetracyclines,chloramphenicol, clindamycin, lincomycin, fusidic acid, novobiocin,fosfomycin, fusidate sodium, capreomycin, colistimethate, gramicidin,minocycline, doxycycline, bacitracin, erythromycin, nalidixic acid,vancomycin, and trimethoprim. The antibiotic may be bacteriocidial orbacteriostatic. Appropriate types of other anti-microbial agents as APIsmay include, but are not limited to, anti-viral agents, anti-protazoalagents, and/or anti-parasitic agents.

Appropriate API anti-inflammatory agents may include, but are notlimited to, corticosteroids (such as, for example, glucocorticoids),cycloplegics, NSAIDs, and/or immune selective anti-inflammatoryderivatives (ImSAIDs).

Appropriate API NSAIDs may include, but are not limited to, celecoxib,rofecoxib, etoricoxib, meloxicam, valdecoxib, diclofenac, etodolac,sulindac, aspirin, alclofenac, fenclofenac, diflunisal, benorylate,fosfosal, salicylic acid including acetylsalicylic acid, sodiumacetylsalicylic acid, calcium acetylsalicylic acid, and sodiumsalicylate; ibuprofen, ketoprofen, carprofen, fenbufen, flurbiprofen,oxaprozin, suprofen, triaprofenic acid, fenoprofen, indoprofen,piroprofen, flufenamic, mefenamic, meclofenamic, niflumic, salsalate,rolmerin, fentiazac, tilomisole, oxyphenbutazone, phenylbutazone,apazone, feprazone, sudoxicam, isoxicam, tenoxicam, piroxicam,indomethacin, nabumetone, naproxen, tolmetin, lumiracoxib, parecoxib,and/or licofelone, including pharmaceutically acceptable salts, isomers,enantiomers, derivatives, prodrugs, crystal polymorphs, amorphousmodifications, and/or co-crystals.

Appropriate types of APIs may include, but are not limited to, agentshaving NSAID-like activity, including, but not limited to, non-selectivecyclooxygenase (COX) inhibitors, selective COX-2 inhibitors, selectiveCOX-1 inhibitors, and/or COX-LOX inhibitors, as well as pharmaceuticallyacceptable salts, isomers, enantiomers, polymorphic crystal formsincluding the amorphous form, co-crystals, derivatives, and/or prodrugsthereof.

Appropriate APIs may alternatively or additionally include, but are notlimited to, adriamycin/bleomycin/vinblastine/dacarbazine (ABVD),avicine, acetaminophen, acetylsalicylic acid, acridine carboxamide,actinomycin, alkylating antineoplastic agent,17-N-allylamino-17-demethoxygeldanamycin, aminopterin, amsacrine,anthracycline, antineoplastic, antineoplaston, antitumorigenic herbs,5-azacytidine, azathioprine, triplatin tetranitrate (BBR3464), BL22,bifonazole, biosynthesis of doxorubicin, biricodar, bleomycin,bortezomib, bryostatin, buprenorphine, busulfan, cabotegravir, caffeine,calyculin, camptothecin, capecitabine, carboplatin, chlorambucil,chloramphenicol, cisplatin, cladribine, clofarabine, cyclophosphamide,cytarabine, dacarbazine, dasatinib, daunorubicin, decitabine,dexamethasone, diazepam, dichloroacetic acid, discodermolide, diltiazem,docetaxel, dolutegravir, doxorubicin, epirubicin, epothilone,estramustine, 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA),etonogestrel, etoposide, everolimus, exatecan, exisulind, fentanyl,ferruginol, floxuridine, fludarabine, fluorouracil, 5-fluorouracil,fosfestrol, fotemustine, gemcitabine, hydroxyurea, ibuprofen,idarubicin, ifosfamide, imiquimod, indomethacin, irinotecan, irofulven,ixabepilone, laminvudine, lapatinib, lenalidomide, liposomaldaunorubicin, lorazepam, lurtotecan, mafosfamide, masoprocol,mechlorethamine, melphalan, mercaptopurine, metformin, methadone,methotrexate, metoclopramide, mitomycin, mitotane, mitoxantrone,naloxone, naproxen, nelarabine, niacinamide, nicotine, nilotinib,nitrogen mustard, oxaliplatin, first procaspase activating compound(PAC-1), paclitaxel, paracetamol, pawpaw, pemetrexed, pentostatin,pipobroman, pixantrone, polyaspirin, plicamycin, prednisone,procarbazine, proteasome inhibitor, raltitrexed, rebeccamycin,rilpivirine, risperidone, ropinirole, 7-ethyl-10-hydroxy-camptothecin(SN-38), salbutamol, salinosporamide A, satraplatin, sildenafil,sirolimus, Stanford V, stiripentol, streptozotocin, swainsonine,tadalafil, taxane, tegafur-uracil, temozolomide, tenofovir,testosterone, tetryzoline, N,N′,N″-triethylenethiophosphoramide(ThioTEPA), tioguanine, tolbutamide, topotecan, trabectedin, trazodone,tretinoin, tris(2-chloroethyl)amine, troxacitabine, uracil mustard,valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, zolpidem,and/or zosuquidar.

In exemplary embodiments, PGSU delivers a sustained release ofhydrophilic, highly-soluble APIs through a surface erosion mechanism,with a crosslinking that limits burst release, percolation, permeation,and diffusion. Crosslinking density may also be tailored for aparticular PGSU degradation rate in order to achieve the desired APIrelease rate.

In exemplary embodiments, PGSU delivers a sustained release ofhydrophobic, poorly-soluble APIs through a surface erosion mechanism,with a crosslinking that limits burst release, percolation, permeation,and diffusion. Crosslinking density is also optimized for a particularPGSU degradation rate in order to achieve the desired API release rate.

Thorough PGS chemical characterization may be critical to thedevelopment of a successful PGSU product with predictable API deliverybehavior. Key physiochemical parameters of the starting polyol thatultimately affect the degradation rate, the release kinetics, and thestability of PGSU have not been previously identified. Namely, polymerarchitecture, molecular weight, polydispersity index, polycondensationreaction conditions, acid number, hydroxyl number, glycerol-sebacic acidstoichiometry, isocyanate-hydroxyl stoichiometry, and crosslinkingdensity may all affect API pharmacokinetics in final PGSU product form.

PGSU is capable of offering a nearly dose-independent API release, wherea higher drug loading does not dramatically impact the relative rate ofrelease of the API. Conventional PGSU drug delivery vehicles do notprovide long-term release and do not address applications where 3-monthto 12-month therapy duration is needed and extremely high drug loadingis necessary in order to maintain the daily therapeutic window for suchsustained periods of time. Conventional PGSU drug delivery vehicles donot address drug loading levels or ways to address the challenges ofachieving high drug loading levels.

In exemplary embodiments, a PGSU composition accommodates API-loadingamounts, based on the total weight of the implantable product, of atleast 10% w/w, alternatively 10% w/w to 90% w/w, alternatively 10% w/wto 40% w/w, alternatively 20% w/w to 80% w/w, alternatively at least 20%w/w, alternatively at least 30% w/w, alternatively at least 40% w/w,alternatively 40% w/w to 90% w/w, alternatively 40% w/w to 80% w/w,alternatively 50% w/w to 80% w/w, alternatively 60% w/w to 80% w/w,alternatively up to 90% w/w, or any value, range, or sub-rangetherebetween, preferably while maintaining substantially zero-order orsubstantially first-order release while achieving a dose-independentrelease rate for more than three months, preferably at least six months,inconceivable without the use of a surface-eroding polymer like PGSU andhistorically unconventional among the commercial space for long-actingimplantables.

In exemplary embodiments, a manufacturing process for an API-containingPGSU product from PGS, isocyanate, and the API does not require the useof solvents or heat, which is advantageous for API delivery. Thepresence of water may quench the isocyanate and prevent effectivecrosslinking. The PGSU reaction from resin to solid does not require anyheat and does not generate any moisture. All components, raw materials,substrates, parts, and surfaces are kept free of moisture. The PGSpolyol may be dried to remove any residual moisture remaining fromsynthesis, whether by drying in an oven, drying in a reactor, or otherdrying method. This ensures that the desired target crosslinking can bemet and no HDI is quenched by water. Conventional PGSU processes do notaddress the challenges related to drying and degassing PGS resin.

In exemplary embodiments, a manufacturing process for an API-containingPGSU product from PGS, isocyanate, and the API employs the use of vacuumto remove generated air bubbles, entrained air, and entrapped air.Conventional PGSU processes do not address the challenges related toremoving air bubbles during mixing and compounding resulting frommoisture, dissolved gasses, and mixing.

In some embodiments, a composition includes a PGSU formulation includingat least one catalyst to accelerate the PGSU reaction. Appropriatecatalysts may include, but are not limited to, catalysts containingmetals and/or catalysts of metal salts. Appropriate catalysts maycontain or include, but are not limited to, tin, caffeine, potassium,sodium, calcium, magnesium, citric acid, citrate in salt form, such as,for example, potassium citrate, tartaric acid, and/or tartrate in saltform, such as, for example, potassium tartrate. The organic acid form ofcitric acid and tartaric acid may participate in crosslinking, while thesalt form of citrate and tartrate may not participate in crosslinking.Appropriate catalysts may be non-toxic, pharmaceutically-friendly,and/or non-interfering with respect to the pharmacokinetics of the PGSU.Catalysts that are salt-based may offer improved biocompatibility,non-toxicity, pharmacokinetic compatibility, and pharmaceuticalacceptance compared to heavy metal-based catalysts, which have strictlimits of exposure in humans.

In some embodiments, an implantable product includes a PGSU formulationincluding at least one additive to improve API release kinetics, improveAPI solubility, improve API permeability, improve product stability,improve product radiopacity, improve PGSU crosslinking kinetics, improvePGSU working time, improve rheological behavior, improve thermalbehavior, improve mold release, or combinations thereof. Appropriateadditives may include, but are not limited to, PGS flour, mannitol,lactose, magnesium stearate, sodium stearate, stearic acid,poly(ethylene glycol) (PEG), triethyl citrate (TEC), barium sulfate,solubility enhancers, permeability enhancers, plasticizers, fillers,binders, disintegrants, catalysts, microparticles, nanoparticles, orcombinations thereof.

As used herein, “PGS flour” refers to a thermoset PGS that has beenprocessed, such as, for example, micronized by grinding, into a powderof fine particle size, such as, for example, less than 1000 microns,such as, for example, as disclosed in U.S. Patent ApplicationPublication No. 2017/0246316, which is hereby incorporated by referencein its entirety.

In some embodiments, a composition includes an isocyanate having analiphatic chemical structure.

In some embodiments, a composition includes an isocyanate having anaromatic chemical structure.

In some embodiments, a composition includes an isocyanate having acombination aliphatic-aromatic chemical structure.

In some embodiments, a composition includes blocked isocyanates thatbecome unblocked upon exposure to a trigger, such as, for example, heat,in order to extend the working time and subsequently improve thehomogeneous API incorporation and the reactant mixing. Blockedisocyanates may be used to delay the reaction until a particulartemperature or other trigger or benchmark is reached. This allowscontrol over when and where the reaction occurs, as opposed to thereaction beginning at the moment of formulation. This strategic delaygrants a longer pot life, affording more time for mixing and more timefor forming, all of which assist manufacturing by offering more freedomin the choice of manufacturing technique, de-risking the compoundingstep, de-risking the molding or extrusion step, allowing morehomogeneous mixing, allowing more homogeneous crosslinking, simplifyingthe manufacturing process, saving time, and/or saving cost. The abilityto trigger the reaction using a blocked isocyanate may also protect theAPI from cross-reaction into the polymer during crosslinking.

In some embodiments, a composition includes an isocyanate-to-hydroxylstoichiometric ratio in the range of 1:0.25 to 1:2, alternatively in therange of 1:0.25 to 1:0.75, alternatively in the range of 1:0.4 to1:0.75, alternatively in the range of 1:0.25 to 1:1, alternatively inthe range of 1:0.25 to 1:1.25, alternatively in the range of 1:0.25 to1:1.5, or any value, range, or sub-range therebetween, to maintain astable product with optical clarity that does not exhibit clouding,hazing, blooming, or stiffening over time upon storage at ambientconditions including room temperature, atmospheric pressure, and roomhumidity. Certain isocyanate-to-hydroxyl stoichiometric ratios less than1:2, such as, for example, 1:3 or 1:4, were found to suffer fromclouding and stiffening when stored in ambient conditions, which isdetrimental to product shelf life. Additionally, conventionalintravitreal injections and implants made of other polymers require coldstorage at −4° C. or −20° C., which may be costly and/or impractical fordrug products.

In some embodiments, a composition includes a polyol reactant composedof at least 50% and up to 100% w/w solids content to minimize oreliminate the use of solvents.

In some embodiments, a composition includes an API loading into anycomponent, partial blend, or complete blend of the PGSU formulation tocreate an implantable PGSU product with up to 90% w/w API content thatachieves a greater than 3-month duration of drug therapy.

In some embodiments, a composition includes a PGSU formulation withrheological properties amenable to mixing, incorporation of an API, andmanufacturing methods.

In some embodiments, a composition includes a PGSU formulation where nopartitioning of API occurs within the polymer matrix due to the APIhaving a strong physical affinity for the matrix chemistry.

In some embodiments, a composition includes a crosslinking density ofpolymerized PGSU of at least 0.8 mol/L, alternatively between 0.8 mol/Land 4.0 mol/L, alternatively between 0.8 mol/L and 3.5 mol/L,alternatively at least 1.0 mol/L, alternatively between 1.0 mol/L and4.0 mol/L, alternatively between 1.0 mol/L and 3.5 mol/L, alternativelybetween 1.0 mol/L and 3.0 mol/L, alternatively between 1.0 mol/L and 2.0mol/L, alternatively between 1.5 mol/L and 4.0 mol/L, alternativelybetween 1.5 mol/L and 3.5 mol/L, alternatively between 2.0 mol/L and 4.0mol/L, alternatively between 2.0 mol/L and 3.5 mol/L, alternativelybetween 2.5 mol/L and 3.5 mol/L, alternatively between 3.0 mol/L and 3.5mol/L, or any value, range, or sub-range therebetween.

In some embodiments, a composition includes a crosslinking density ofpolymerized PGSU between 0.5 mol/L and 3.5 mol/L, to minimize, reduce,or eliminate clouding and hazing during shelf life storage.

In some embodiments, a composition includes a crosslinking density ofpolymerized PGSU between 1.5 mol/L and 3.5 mol/L, to minimize, reduce,or eliminate permeation, percolation, burst release, and/or diffusion.

In preferred embodiments, PGSU has a swellability below 5% w/w in salinesolution at 23° C. or 37° C. over the course of two weeks, which reducespermeation, percolation, burst release, and diffusion in a highly APIloaded implant. Conventional processes describe swelling to be 5-10% w/win saline solution at 37° C. for 24 hours for solvent-based PGSU atlower crosslinking densities than described here. Conventionalprocesses, aiming to improve water uptake by PGSU by incorporating drugloading rather than decrease water uptake by PGSU with high drugloading, describe swelling to be 5% w/w, 30% w/w, and 80% w/w in salinesolution for 24 hours for solvent-free PGSU, solvent-free PGSU loadedwith 25% w/w BSA, and solvent-free PGSU loaded with 25% w/wBSA-trehalose, respectively, at lower crosslinking densities thandescribed herein.

In preferred embodiments, PGSU has a sol content below 5% w/w under 24hours of tetrahydrofuran (THF) swelling, which is important to reduceextractables, reduce blooming of sol fractions to the surface, reduceAPI migration to the surface, reduce burst release, prolong shelf lifestability, and prevent biocompatibility issues. Conventional processesdescribe sol content to be 10-20% w/w under 24 hours of ethanol swellingfor solvent-based PGSU at lower crosslinking densities than describedherein.

Engineering properties of preferred forms of an implantable product fordelivery and in vivo service may include a flexible, elastomericproduct, as indicated by hardness, flexural modulus, compressivemodulus, and tensile modulus, that reduces patient discomfort, reducespropensity for fracture during normal patient movement, conforms toanatomical geometry, such as, for example, anatomical topography orcurvature, and closely matches the mechanical properties of human tissueat the implant location, such as the inner upper arm where adipose andmuscle tissue can vary greatly based on gender, age, race, fitnesslevel, hydration level, and pre-existing health conditions. Having animplant with mechanical properties that minimize compliance mismatchwith native tissue may temper inflammatory response and preventfibrosis.

Other engineering properties of preferred forms of an implantableproduct for delivery and in vivo service may include an easilydeliverable product without high friction, buckling, or kinking duringdeployment from a delivery device.

In preferred embodiments, unloaded PGSU has a flexural modulus greaterthan 4 MPa, an elastic compressive modulus greater than 25 MPa, and anelastic tensile modulus greater than 4 MPa. Conventional processesdescribe an elastic tensile modulus less than 10 MPa for solvent-freePGSU and less than 20 MPa for solvent-based PGSU, and elongations up to125% for solvent-free PGSU and up to 520% for solvent-based PGSU. Toobtain theses values in conventional processes, all PGSU samples wereimmersed in saline for 24 hours at 37° C. prior to testing, whichremoves the unreacted low molecular weight fractions that otherwiseserve as plasticizer, and solvent-based PGSU samples were additionallyimmersed in ethanol for 24 hours to intentionally swell the matrix andremove sol content, which similarly serves as plasticizer (see Pereiraet al., “A Highly Tunable Biocompatible and MultifunctionalBiodegradable Elastomer”, Adv. Mater., Vol. 25, pp. 1209-1215, 2013).Accordingly, these conventional process mechanical property valuesreflect a stiffer PGSU than PGSU without any processing, and as suchcannot be directly compared to mechanical property values describedherein. Conventional processes aimed to improve the tensile elongationand tensile cycling of PGSU, not optimize flexural properties best forpatient comfort and implant deployment like described herein. LoadedPGSU, however, may have a significantly different flexural modulus,elastic compressive modulus, and elastic tensile modulus.

Other engineering properties of preferred forms of an implantableproduct for delivery and in vivo service may include surface erosion asthe mechanism of API release in order to achieve a release rate that isindependent of API loading concentration.

Other engineering properties of preferred forms of an implantableproduct for delivery and in vivo service may include a product withinitial water-impermeability, in order to eliminate API release that isdriven by a concentration gradient between the polymer matrix andsurrounding environment.

Other engineering properties of preferred forms of an implantableproduct for delivery and in vivo service may include a product that maybe tuned to a desired degradation rate and corresponding API releaserate using the physiochemical properties of the PGSU. Suchphysicochemical properties may include, but are not limited to, theglycerol-to-sebacic acid stoichiometric ratio, the hydroxyl number, theacid number, the isocyanate-to-hydroxyl stoichiometric ratio, themolecular weight, the crosslinking density, or combinations thereof.

Other engineering properties of preferred forms of an implantableproduct for delivery and in vivo service may include a duration oftherapy greater than 3 months while maintaining plasma concentrations ina therapeutic window, afforded by a high drug loading in combinationwith the surface erosion of PGSU.

Other engineering properties of preferred forms of an implantableproduct for delivery and in vivo service may include a reduced lag uponthe start of therapy and a reduced tail upon the end of therapy,afforded by surface erosion of PGSU.

Other engineering properties of preferred forms of an implantableproduct for delivery and in vivo service may include retrievability forgreater than one month post-implantation, in the event of an adversereaction, for example.

Other engineering properties of preferred forms of an implantableproduct for delivery and in vivo service may include PGSU orbiodegradation byproducts that do not interfere with API absorption,distribution, metabolism, excretion characteristics, or combinationsthereof.

Other engineering properties of preferred forms of an implantableproduct for delivery and in vivo service may include PGSU orbiodegradation byproducts that do not impact API solubility,permeability, hygroscopicity, thermal stability, hydrolytic stability,photostability, or combinations thereof.

Other engineering properties of preferred forms of an implantableproduct for delivery and in vivo service may include PGSU orbiodegradation byproducts that do not modify an API free acid, an APIfree base, an API salt form, an API crystallinity, an API amorphism, orcombinations thereof and/or do not induce any polymorphic changes.

Other engineering properties of preferred forms of an implantableproduct for delivery and in vivo service may include PGSU orbiodegradation byproducts that are non-immunogenic and that do notincite an inflammation that would interfere with the API release rate.

A deployment method and mode may provide a product assembled into adelivery device, such as, for example, a needle, a cannular, anapplicator, a trocar, or combination thereof.

A deployment method and mode may provide deployment of an implantableproduct with the application of a local anesthetic.

A preferred process may include reacting a polyol and an isocyanatetogether using a compounding method that eliminates any air voids. Apreferred process may include incorporation of the API pre-reaction,using compounding methods to allow API loading up to 90% w/w solids.Appropriate compounding methods may include, but are not limited to,static mixing, shear mixing, vacuum mixing, twin screw mixing, venturimixing, or combinations thereof.

A preferred process may include incorporating the API post-reaction,using an infusion method and/or protecting the API during incorporationpre-reaction, in order to prevent cross-reaction of API into the PGSUmatrix during polymerization, in the event an API has susceptible andsterically-accessible functional groups that may participate in covalentbond formation, which may either affect API bioavailability or PGSUcrosslinking and degradation.

A preferred product manufacturing process may include reaction injectionmolding, casting, molding, spray coating, spin coating, electrospinning,additive manufacturing, extrusion, or combinations thereof.

A preferred product manufacturing process may include using a die with agradient or particular architecture that is designed to achieve specificAPI release kinetics.

A preferred product manufacturing process may include forming acylindrical rod-shaped product with a higher API loading in the center,in order to achieve a more linear first-order API release rate, as thediameter decreases during surface erosion of PGSU. In contrast, a firstorder release rate is better maintained for rectangular film shapes, asthe thickness decreases during PGSU surface erosion.

A preferred product manufacturing process may include using mild shearand friction conditions that do not affect API properties.

A preferred product manufacturing process may include solventevaporation that is limited, slowed, or controlled to prevent APIaggregation, phase separation, or partitioning during the solventevaporation step.

A preferred product manufacturing process may include solventevaporation post-reaction at low heat conditions, such as less than 60°C. (140° F.), that do not affect API properties in cases where a solventis employed in the process, such as to reduce viscosity.

A preferred product manufacturing process may include application of lowheat conditions, such as less than 40° C. (104° F.), that do not affectAPI properties in cases where heat is employed in the process, such asto reduce viscosity.

In other embodiments, the product manufacturing process may includecooling conditions, such as less than 20° C. (68° F.), before, during,or after mixing, to slow the reaction and avoiding or reducing thelikelihood of clogging the injection molding equipment.

A preferred product manufacturing process may preserve all constraintson stoichiometry, degradation rate, and tissue compliance properties ofa PGSU composition.

A preferred product manufacturing process may include the compoundedlevel of API remaining present at a prescribed level, within UnitedStates Pharmacopeia (USP) standards, following the manufacturingprocess.

Exemplary embodiments provide predictable and reliable API releasekinetics across PGSU chemical parameters as well as at different drugloadings. In exemplary embodiments, the implantable product includes aPGSU cylindrical rod formed from a highly-branched PGS resin createdfrom a water-mediated polycondensation reaction. In some embodiments,the PGS resin includes a polydispersity index of about 8, a molecularweight of about 15,000 Da, an acid number of about 43, a hydroxyl numberof about 200, and about 1:1 stoichiometric ratio of glycerol-to-sebacicacid. The PGS resin is warmed to about 37° C. (98.6° F.) andhomogeneously mixed under vacuum with about 60% w/w API, followed byfurther homogeneous mixing under vacuum with about 0.1% w/w tin(II)2-ethylhexanoate catalyst. A flowable resin is created without asolvent. Alternatively, a PGS solution may be prepared at about 60% w/win 1:1 (w/w) acetone-to-propyl acetate solvent in order to achieveflowability at about 23° C. (73.4° F.) and to increase the working time.The PGS-API-catalyst blend is then combined with aliphatic HDI at anisocyanate-to-hydroxyl stoichiometric ratio of about 1:0.6 using vacuummixing. The mixture is then quickly transferred into a syringe and theninjected into a 2-mm to 3-mm inner diameter tubing to cast the finalcylindrical rod form. The set-to-touch time is a few minutes, and thefilled molds are kept at about 23° C. (73.4° F.) for about 24 hours toset fully. The crosslinking is complete once substantially all of theHDI has been reacted, and additional processing is not necessary. Inprocesses using solvent to improve PGS flowability, the rods are placedin a 40° C. (104° F.) oven for about 6 days to ensure complete solventevaporation to below 0.5% w/w loss on drying after the initial 24 hoursat about 23° C. (73.4° F.).

In exemplary embodiments, the reaction injection molding parameters areselected to achieve solvent-free, low-temperature, high-throughputmanufacture with homogeneous compounding across a range of viscosities.The throughput of a reaction injection molding system may be dependenton die design and parallelizability of injection. Homogeneous blendingand API incorporation may be dependent on the viscosity, the flow rateinto the mixing chamber, and the method of mixing. In exemplaryembodiments, the API and the catalyst are pre-mixed into the PGS resin,and mixing is maintained as the material is routed to a mixing chamber,where it is combined with isocyanate within seconds and quickly injectedunder pressure into a die for forming.

In exemplary embodiments, a two-component mixing and metering unit forPGSU reaction injection molding includes two positive displacementmetering pumps with flow and ratio adjustability, such as, for example,a servo-controlled progressive cavity or servo-controlled spur gear withvolumetric proportioning; two supply vessels of suitable capacity formaterial feeding, such as, for example, pressurized tanks with bandheaters, electric agitators, and vacuum kits; a static or dynamic mixingapplicator, such as, for example, a dynamic mixing valve withcirculation of both components, drive unit with pneumatic motor,non-return valves, and pneumatic and hydraulic fittings; a vacuum pumpwith control interface, such as, for example, a vacuum pump with vacuumsensors on all tanks and pneumatically operated valves; and anelectronic control package.

In some embodiments, PGSU may be extruded using a single screw extruder,a twin screw extruder, a microcompounder, a dual-barrel cartridge,single batch reaction injection molding, or continuous recirculatingreaction injection molding. Mixing of one or more components may occurprior to introduction to the compounding equipment, such as, forexample, using a speedmixer, an overhead mixer, a dynamic mixer, ahigh-shear mixer, and/or a 3-roll mill. One or more mixing steps mayoccur in the barrel, tubing, chamber, tip, and/or nozzle of thecompounding equipment and may be either static or dynamic. Addition ofthe isocyanate into the various equipment is carefully designed, sincehomogeneous isocyanate incorporation is desirable for even crosslinking,and the isocyanate and catalyst should be kept physically separateduntil it is desired to initialize the PGSU reaction. In someembodiments, the PGSU reaction may begin to occur inside the equipment,but the material will not become solid or semi-solid until it has exitedthe equipment, allowing for the PGSU blend to remain liquid, flowable,and mixable inside the equipment. In some embodiments, the PGSU reactionmixture may be recirculated inside the equipment until the monitoredviscosity reaches a designated point, after which the PGSU blend isallowed to exit the equipment. In some embodiments, the PGSU reactiondoes not occur until the isocyanate and catalyst components meet in amixing chamber, a tip, or a nozzle, and prior to this point theisocyanate and catalyst are kept physically separated. In someembodiments, the PGSU reaction does not occur until the PGSU blend exitsthe equipment. In some embodiments, the PGSU may be fabricated usingheat to accelerate and properly time the curing at the point of exitfrom the nozzle or die. The PGSU may be drug-loaded at the time offorming. Alternatively, the PGSU may be infused or soaked with API afterforming.

In some embodiments, high shear mixing is required to evenly distributeand fully incorporate isocyanate into the PGS resin, such as, forexample, by using mixing media and/or grinding media in concert withother mixing methods, such as, for example, using a speedmixer, anoverhead mixer, a dynamic mixer, a high-shear mixer, and/or a 3-rollmill. Mixing may also occur in the compounding equipment, such as, forexample, a single screw extruder, a twin screw extruder, amicrocompounder, a dual-barrel cartridge, single batch reactioninjection molding, or continuous recirculating reaction injectionmolding, where mixing may occur in the barrel, tubing, chamber, tip,and/or nozzle and may be either static or dynamic. Homogeneousdistribution and complete incorporation of isocyanate into the PGSUblend is challenging due to the disparate viscosities of isocyanate andPGS resin, the high volumes of isocyanate in order to achieve highcrosslinking densities, and the immiscibility of isocyanate with PGSresin. However, homogeneous distribution and complete incorporation ofisocyanate is desirable in order to achieve the target crosslinkdensities and PGSU degradation rates needed for sustained drug release.

In some embodiments, high shear mixing is desirable to evenly distributeand fully incorporate API into the PGS resin, for example, by usingmixing media and/or grinding media in concert with other mixing methods,such as, for example, using a speedmixer, an overhead mixer, a dynamicmixer, a high-shear mixer, and/or a 3-roll mill. Mixing may also occurin the compounding equipment, such as, for example, a single screwextruder, a twin screw extruder, microcompounder, a dual-barrelcartridge, single batch reaction injection molding, or continuousrecirculating reaction injection molding, where mixing may occur in thebarrel, tubing, chamber, tip, and/or nozzle and may be either static ordynamic. Homogeneous distribution and complete incorporation of API intothe PGSU blend is challenging due to the high viscosity of PGS resin,bulk density of APIs, large masses of API necessary to achieve high drugloadings, and sometimes poor wettability of APIs by PGS resin. However,homogeneous distribution and complete incorporation of API is desirableto achieve the target drug loading, content uniformity, and particledistribution needed for sustained drug release.

In some embodiments, heat may be applied to reduce PGS viscosity so thatPGS components are flowable and manufacturable and so that homogeneousmixing with isocyanate and API may be achieved. PGS blended withisocyanate was found to prematurely solidify, even in the absence ofcatalyst, if exposed to temperatures greater than 60° C. for more than afew minutes. PGS blended with isocyanate was found to prematurelysolidify, even in the absence of catalyst, if held at 23° C. for 24hours. PGS blended with isocyanate was found to prematurely solidify,even in the absence of catalyst, if held at −20° C. for greater than 48hours. Thus, PGS blended with isocyanate, in the absence of catalyst, isbest maintained below 40° C. and used within a few hours of mixing. Insome embodiments, heat may be applied to accelerate or time the PGSUreaction. Due to the importance of heat for viscosity reduction and/orreaction timing, torque rheology trials were performed on PGS resinblended with isocyanate and catalyst to determine how the PGSU reactionkinetics change across temperatures ranging from 40° C. to 80° C.

In some embodiments, heat may be applied after forming PGSU into a solidin order to force complete reaction of the isocyanate since residualisocyanate has been linked with irritation and sensitization in vivo.This is especially important at high crosslinking densities where theisocyanate is present in excess of the polyol, such as, for example,when isocyanate-to-hydroxyl stoichiometric ratios are between 1:0.25 and1:0.9. It was found that heating PGSU implants at 40° C. immediatelyafter forming or 24 hours after forming helped drive the isocyanate toreact completely, leaving no residual isocyanate behind after 24 hoursof this mild heat exposure. Without added heat, at 23° C., this processof fully reacting the isocyanate required 72 to 96 hours.

In other embodiments, PGS resin, catalyst, and isocyanate form PGSU inan additive manufacturing application, such as a three-dimensional (3D)printing application. Various additive manufacturing methods, including,but not limited to, fused deposition modeling, selective lasersintering, material extrusion, bioprinting, stereolithography, digitallight processing, digital light synthesis (continuous liquid interfaceproduction), inkjet printing, or material jetting, may be suitable forPGSU, depending on the chemistry, viscosity, and polymerizationkinetics. In some embodiments, a dual barrel 3D printer combines thePGS-API-catalyst blend with HDI right at the nozzle prior to layerextrusion. In some embodiments, a single barrel 3D printer directs aPGSU formulation with a working time greater than the time needed toprint an entire barrel volume, such as, for example, 20 minutes for a10-cc syringe volume. Fillers and/or plasticizers may be included tomodify the PGSU formulation viscosity, and API incorporation may impactthe rheology as well. The ability to additively manufacture PGSU opensmany other possibilities, such as, for example, patient-specificimplantable products and designs, complex geometries with internalstruts and voids, manufacturing-on-demand to reduce a stability testingburden and equipment costs, and multi-material constructs withco-delivery of multiple APIs having different release kinetics fromtuned PGSU formulations.

In other embodiments, PGSU formulations for sustained release may becomposed of complex geometries with different compartments, such ascore-sheath rods, where the sheath acts as a barrier to preventdiffusion or burst release, or where the sheath is loaded with drug toprovide an initial purposeful burst release to reach therapeutic plasmaconcentrations quickly. Different compartments may contain differentAPIs or different API concentrations or have different crosslinkingdensities to achieve different degradation rates. Multi-compartment,multi-modal, or multi-drug PGSU designs may be used for drug deliverythrough transdermal, parenteral, subcutaneous, intramuscular,intraocular, intravitreal, intraarticular, intravaginal, buccal, orgastrointestinal routes of administration.

In other embodiments, PGSU complex geometries may includemicroparticles, nanoparticles, microspheres, nanospheres, multi-layeredspheres, multi-compartment particles, and/or shaped particles for thepurpose of drug delivery through transdermal, parenteral, subcutaneous,intramuscular, intraocular, intravitreal, intraarticular, intravaginal,buccal, or gastrointestinal routes of administration. PGSU microspheresmay be fabricated using a dual-chamber spray coater nozzle and sprayingthe blended PGSU formulation into air, onto a substrate, or into asolvent, for size control and collection. PGSU microspheres may befabricated using emulsion technology and heat to accelerate and properlytime the curing. PGSU microspheres may be unloaded or drug-loaded andmay be fabricated across a variety of crosslinking densities. PGSUmicrospheres may be infused or soaked with API after forming. PGSUmicrospheres may be coated with API powder, API solution, or anAPI-polymer blend after forming. PGSU microspheres may be fused togetherafter being formed to create various shapes. PGSU microspheres may beformulated to aggregate or cluster together once injected into the body,to create a depot for sustained release.

In other embodiments, PGSU complex geometries may include fibers, yarns,knits, weaves, braids, and/or fibrous mats, using, for example,extrusion, wet spinning, fiber drawing, fiber pulling, orelectrospinning. PGSU fibers may be extruded using a single screwextruder, a twin screw extruder, a microcompounder, a dual-barrelcartridge, single batch reaction injection, or continuous recirculatingreaction injection. In some cases, PGSU fibers may be fabricated usingheat to accelerate and properly time the curing at the point of exitfrom the nozzle or die. PGSU fibers may be drug-loaded at the time offorming. Alternatively, PGSU fibers may be infused or soaked with APIafter forming. Drawing down PGSU fibers may convey an orientation of thepolymer chains, before the curing is complete, which allows bettersurface properties, higher strength, more homogeneous mesh size, morecontrolled drug release, more controlled degradation, and/or lessinflammatory response. In some embodiments, PGSU fibers may have acircular cross-section. Alternatively, PGSU fibers may have a shapedcross-section that dictates PGSU degradation behavior, drug loadingefficiency, and drug release kinetics. PGSU's surface erosion changeswith fiber cross-section shape due to surface area-to-volume ratiochanges, since water and enzymes need to have access to the polymerbefore hydrolytic and enzymatic degradation can occur, respectively.Drug diffusion out of the matrix changes with fiber cross-section shapedue to the different path lengths in the matrix that the drug travelsthrough during release. Drug adsorption onto the matrix during loadingchanges with fiber cross-section shape due to different surface areasbeing exposed during coating. Drug infiltration into the matrix changeswith fiber cross-section shape due to different surface areas beingexposed and different path lengths in the matrix that the drug travelsthrough during infusion or soaking. All of these phenomena result in adrug release that is dependent on fiber cross-section shape. The resultis a highly-tunable system where drug loading, drug release, and/orpolymer degradation may be augmented by merely changing the shape of thedie during PGSU fiber extrusion.

In other embodiments, PGSU complex geometries may include microneedlesand microneedle patches for the purpose of drug delivery throughtransdermal, parenteral, subcutaneous, intramuscular, intraocular,intravitreal, intraarticular, intravaginal, buccal, or gastrointestinalroutes of administration.

In other embodiments, PGSU may be combined with textile technology tocreate textile patches, wearable textiles integrated into clothing,textile sensors, or implantable textiles for the purpose of drugdelivery through transdermal, parenteral, subcutaneous, intramuscular,intraocular, intravitreal, intraarticular, intravaginal, buccal, orgastrointestinal routes of administration.

In other embodiments, PGSU may be formulated for in situ gelation, wherea dual-barrel cartridge keeps the isocyanate and catalyst physicallyseparated until the two components meet in a mixing chamber, tip, ornozzle, and the PGSU blend is delivered into the body. The timing of thecure, for example, may be slow or rapid, may be driven by urethanechemistry or ionic interactions with the in vivo environment, and/or mayproduce a liquid, semi-solid, or solid depot for drug delivery, tissueregeneration, cellular infiltration, cellular delivery, lubrication,viscosupplementation, mechanical dampening, mechanical support,mechanical blocking, anti-inflammatory treatment, and/or anti-bacterialtreatment.

In other embodiments, PGSU may be made into a foam or porous scaffoldusing a controlled gas-foaming process. Air bubbles may be introduced bypurposefully introducing moisture during the PGSU reaction.Alternatively, air bubbles may be introduced by mixing PGSU with highshear in the absence of vacuum, causing air entrainment. Alternatively,air bubbles may be introduced by extruding PGSU with a twin screwextruder, which is typically run with open headspace, causing airentrainment. Alternatively, air bubbles may be introduced into PGSU byformulating in a surfactant or an air-entraining agent.

In other embodiments, PGSU is intended to be solid without any airbubbles or voids. Air bubbles may be eliminated by performingdispensing, mixing, compounding, and/or forming steps under vacuum toavoid air entrainment. Alternatively, the pouring, filling, molding, orforming process may be performed under vacuum to avoid air entrapment,which causes large bubbles and voids. Alternatively, air bubbles may beeliminated by dispensing, mixing, compounding, and/or forming undercentrifugation. Alternatively, air bubbles may be eliminated byperforming dispensing, mixing, compounding, and/or forming undersonication. Alternatively, air bubbles may be eliminated by formulatingin a surfactant, degassing agent, or moisture removal agent.Alternatively, air bubbles may be eliminated by using low-viscositycomponents, such as, for example, solvated PGS or heated PGS to reduceviscosity, which allows air bubbles to self-eliminate and flow out moreeasily. Alternatively, air bubbles may be eliminated by using low shearmixing, since high shear mixing may cause air entrainment and air bubblecoalescence. Alternatively, air bubbles may be eliminated by using highshear mixing under vacuum. Alternatively, the PGSU reaction may bedriven more quickly using heat to prevent air bubble coalescence.Alternatively, air bubbles may be eliminated by keeping all components,raw materials, substrates, parts, and surfaces degassed and free ofmoisture. PGS resin is formed by a polycondensation reaction whichinherently produces some water; however, this moisture may be removedwith vacuum during PGS resin synthesis. The PGS polyol may be driedfurther to remove any residual moisture remaining from synthesis,whether by drying in an oven, drying in a reactor, or drying by anotherdrying method. The method of PGS resin synthesis, whether using awater-mediated process or not, may impact the residual moisture anddissolved gasses in the PGS resin. Parameters such as stirring speed,stirring blade design, reactor dimensions, nitrogen flow rate, vacuumpressure, reaction duration, reaction temperature, reactor insulation,ambient temperature, solubility of starting materials glycerol andsebacic acid, order of addition of starting materials glycerol andsebacic acid, and/or timing of addition of starting materials glyceroland sebacic acid may all impact residual moisture content and dissolvedgasses content.

In other embodiments, PGSU geometries may have small or large moleculeAPIs conjugated, tethered, tethered with a cleavable linkage,nonspecifically adsorbed, ionically complexed, embedded, encapsulated,or otherwise located on the PGSU surface, located within the PGSUmatrix, or located within various PGSU compartments and geometries,resulting in different drug release rates. PGSU degradation rate may betailored to achieve different surface erosion timelines, for example, bytailoring the glycerol-to-sebacic acid stoichiometric ratio,isocyanate-to-hydroxyl stoichiometric ratio, and/or molecular weight,which may confer complex drug release profiles when combined with thesevarious drug-loading techniques. Agents that accelerate or deceleratedegradation, for example, by activating and/or recruiting enzymes and/ormacrophages, may also be included in specific compartments to furtherrefine the PGSU degradation profile. Agents that dampen or hinderinflammation may also be included in specific compartments to modulateinflammatory response throughout various stages of the implant lifetime.

In other embodiments, a cleavable linkage may be incorporated into thePGSU polymer backbone to provide additional scission sites forcontrolled degradation, such as, for example, enzyme-mediateddegradation. The cleavable linkage may be a peptide sequence that actsas a binding and cleavage site for a general enzyme, such as lipase oresterase, or a site-specific enzyme, such as matrix metalloproteinase-2(MMP-2) or matrix metalloproteinase-9 (MMP-9).

In other embodiments, PGSU may be blended with other elastomers, suchas, for example, silicone, polyurethane, thermoplastic polyurethane,and/or EVA, to lend biodegradable behavior to these otherwisenon-degradable polymers.

In other embodiments, PGSU may be blended with thermoplastics, such as,for example, PLA, PGA, PLGA, PCL, and/or PEG, to lend softness,compliance, and elasticity to these otherwise stiff degradable polymers,and to lend surface-eroding properties to these otherwise bulk erodingpolymers.

In other embodiments, PGSU may be blended with PGS crosslinked by othermechanisms, such as, for example, thermosetting, cationic UV curing,acrylate UV curing, visible-light curing, infrared-light curing,microwave curing, any other electromagnetic radiative curing, ionicgelation, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) chemistry,EDC/N-hydroxysuccinimide (NHS) chemistry, and/or click chemistry.Alternatively, PGSU may be blended with uncured PGS resin.Alternatively, PGSU may be blended with PGS flour, which is created bythermosetting PGS and cryomilling down to a predetermined particle size.

In other embodiments, PGSU's surface erosion behavior allows the implantto be retrievable for a much longer proportion of the implant lifetime,compared to bulk eroding polymers, which become soft and diffusethroughout the implant volume early on, since surface eroding PGSUremains in one piece until the very end of its degradation pattern.Retrievability is important in the instance where a patient has anadverse reaction to the API or polymer, needs to receive oral orintravenous therapy that is contraindicated with the drug delivered bythe implant, needs to receive oral or intravenous therapy that cannotadditively stack with the dose delivered by the implant, or otherwiseneeds emergency removal of the implant for any reason.

In other embodiments, PGSU's surface erosion behavior allows a rapidonset of degradation at the end of the implant lifetime, avoiding thetail effect that commonly affects non-eroding polymers and avoiding dosedumping that commonly affects bulk eroding polymers. In non-degradableimplants, plasma API concentrations eventually become sub-therapeuticafter most of the API has diffused out, leaving behind a very weak APIconcentration gradient, which causes diffusion of the final amount ofAPI to occur very slowly. This tail effect may last weeks, and if thebulk eroding implant is not retrievable at this point, the patient isunprotected or untreated during these weeks until a new implant cansafely be deployed without any risk of additive dose stacking. Moreover,the API itself may have a very long wash out period, which adds furtherdelay in protection or treatment until a new implant can beadministered. In bulk-eroding implants, the polymer matrix eventuallybecomes diffuse throughout its volume and all the remaining API diffusesout at once. This dose dumping can lead to super-therapeutic and evendangerous plasma API concentrations. With surface eroding implants likePGSU, at the end of the implant lifetime, the API concentration gradientis still strong, since the distribution of API in the center core is thesame as the outside edge, if homogeneous mixing has been achieved. Atthe point where only a small section of the implant is left followingsteady erosion, for example, the width of two or three API particles,the remaining API may quickly diffuse out, leaving behind a highlyporous section of implant with an incredibly high surface area. Sincethe rate of hydrolytic and enzymatic degradation increases withincreasing surface area, having a highly porous PGSU triggers a rapiderosion to 100% degradation. The benefit of hydrophobic, surface-erodingPGSU is that this rapid onset degradation does not occur until themajority of the implant volume has already eroded away, since watercannot otherwise access the implant interior.

In preferred embodiments, PGSU with high crosslinking, such as, forexample, an isocyanate-to-hydroxyl stoichiometric ratio between 1:0.25and 1:1.25, results in an implantable polymer with reduced inflammatoryresponse, complement activation, cellular attachment, and/or fibrousencapsulation compared to less crosslinked PGSU, due to fewer freefunctional groups present on the surface, such as, for example, freecarboxylate groups that are known to activate complement factors.Increasing the crosslinking density of PGSU increases the incidence ofbond formation between functional groups, reducing the number of free,unbound functional groups that may aggravate and/or activate immunecells, circulating cells, and/or local cells. Reducing or eliminating apersistent inflammatory response leads to lower incidence of fibrosisand/or fibrous encapsulation, which otherwise hinders drug releaserates, drug permeation into target tissues, drug distribution withintarget tissues, patient comfort, patient mobility, implant retrieval,and/or implant location identification. Particularly as the PGSU surfaceerodes, if the high degree of crosslinking is homogeneous throughout theimplant volume and the cleaved bonds that become exposed duringdegradation are benign, the PGSU implant material remains biocompatibleand non-inflammatory throughout the lifespan of the implant, leavingbehind minimal changes to the underlying tissue once 100% degradation isreached. Conventional processes describe how increasing PGSUcrosslinking reduces cell attachment after 24 hours from 50% to 20%,when crosslinking is increased from an isocyanate-to-hydroxylstoichiometric ratio of 1:5 to a ratio of 1:1.5. In preferredembodiments, PGSU with an isocyanate-to-hydroxyl stoichiometric ratiobetween 1:0.25 and 1:1.25 may have further reduced cell attachment,creating a PGSU implant that has minimal biological interaction withsurrounding tissues and a more efficient drug release that is unhinderedby cellular attachment and growth. Conventional processes alsodemonstrate foreign body response, inflammatory cell infiltration, andfibrous encapsulation persisting from 1 week through 40 weeks for PGSUwith lower crosslinking densities having an isocyanate-to-hydroxylstoichiometric ratio in the range of 1:1.5 to 1:5. In preferredembodiments, PGSU with an isocyanate-to-hydroxyl stoichiometric ratiobetween 1:0.25 and 1:1.25 demonstrates a zero-to-minimal inflammatorycell presence, minimal fibroplasia, and no fibrous encapsulation after12 weeks of implantation. Additionally, in preferred embodiments, PGSUwith an isocyanate-to-hydroxyl stoichiometric ratio in the range of1:0.25 and 1:1.25 demonstrates zero cytotoxicity, zero acute systemictoxicity, zero irritation, zero subcutaneous implantation side effects,and zero intramuscular implantation side effects, per InternationalOrganization for Standardization (ISO) 10993 and USP Class VI testmethods. Intramuscular implantation was carried out for 120 hours, whilesubcutaneous implantation was carried out for 7 days, and side effectsassessed included clinical signs of toxicity, body weight, macroscopicevaluation for hemorrhaging, necrosis, discoloration, and infection, andfibrous encapsulation measurement.

In other embodiments, PGSU degradation products are anti-microbial, sothat as the long-acting implantable breaks down, the local tissueenvironment has protection from infection on a long-term scale. In otherembodiments, or in combination with the previous embodiment, unreactedPGSU low molecular weight oligomers and monomers are anti-microbial,such that upon swelling after implantation when these species arereleased as a bolus mass loss, the local tissue environment hasprotection from infection on a transient, short-term scale.

In other embodiments, a PGSU method of mixing and manufacture offersprecision in urethane bond distribution, avoiding nitrogen clusters thatmay otherwise be present with poor mixing and that may cause unfavorablebiological responses in poorly-mixed PGSU and poorly-mixed PGSUdegradation products. The urethane bond nitrogen distribution has beenconfirmed to be uniform using infrared spectroscopy by interrogatingdifferent regions of PGSU films and also by generating micron-resolutionheat maps of PGSU film surfaces.

The processes and compositions described herein may be included in anyapplication that benefits from a biodegradable elastomer, such as, forexample, cell scaffolds, textile filaments, microparticles, drug elutingstents, drug eluting textiles, 3D printing, medical devices,pharmaceuticals, drug products, combination device products, technicalfabrics, food products, dermocosmetics, dental products, nutraceuticals,consumer devices, vehicle components, microtome sectioning, gaskets,tubing, sheets, insulation, seals, adhesives, containers, or cookware.

EXAMPLES

The invention is further described in the context of the followingexamples which are presented by way of illustration, not of limitation.

Example 1

PGS resins synthesized by a water-mediated process were compared to PGSresins synthesized by a non-water-mediated process. FIG. 1 shows theviscosity as a function of reaction time for the water-mediated process(10) compared to the non-water-mediated process (20).

PGS resins synthesized by a water-mediated process and PGS resinssynthesized by a non-water-mediated process were characterized andanalyzed. Four different batches of water-mediated PGS resins and fourdifferent batches of non-water-mediated PGS resins, having aweight-average molecular weight (M_(w)) over the range of about 10 kDato about 50 kDa, were characterized. Table 1 shows the resulting datafrom the characterizations. Resins 1-4 were formed by a water-mediatedprocess, and Resins 5-8 were formed by a non-water-mediated process.

TABLE 1 Water-mediated vs. Non-water-mediated PGS Sample Data M_(w) byGPC Zero-Shear Viscosity Polydispersity Acid Sample (Da) (Pa · s) IndexNumber Resin 1 13275 3.06 9.989 47 Resin 2 22817 5.23 11.192 44 Resin 327554 6.11 12.707 43 Resin 4 47058 11.6 21.37 42 Resin 5 11082 2.926.074 50 Resin 6 21155 5.47 10.597 43 Resin 7 27258 7.43 13.132 42 Resin8 50243 23.3 28.032 39

The data in Table 1 shows that the water-mediated PGS had a slightlylower zero-shear viscosity at the low molecular weight end and azero-shear viscosity of about half at the high molecular weight end incomparison to the non-water-mediated PGS. Although the water-mediatedPGS had a higher polydispersity index (PDI) at the low molecular weightend relative to the non-water-mediated PGS, the water-mediated PGS had arelatively lower PDI at the high molecular weight end. The measured acidnumber decreased more significantly with increasing molecular weight forthe non-water-mediated PGS than the water-mediated PGS.

FIG. 2 shows Fourier-transform infrared (FTIR) spectra for the eightresins. No dramatic differences were observed by FTIR between PGSresins, despite the crosslinked PGSU products exhibiting distinctlydifferent physical properties, behaviors, reaction kinetics, andcrosslinked network structure, as demonstrated in the followingExamples. The small peak at about 1210 cm⁻¹ in FIG. 2 is attributed tocrystallinity differences and has been shown to vary with resintemperature and storage and is not believed to be important for chemicalfunctionality.

FIG. 3 shows the gel permeation chromatography (GPC) of PGS Resin 4 (30)and PGS Resin 8 (40). In the non-water-mediated resin, despite having ahigher overall M_(w), there is a lower proportion of mid M_(w) fractionsand higher proportion of low M_(w) fractions. This is reflective ofmonomer, oligomer, and low M_(w) fractions which do not get a chance toreact in the non-water-mediated process. In the water-mediated process,these fractions can react due to the initial retardation caused by theaddition of water. This results in a higher proportion of mid M_(w)fractions and a lower proportion of low M_(w) fractions. This shift inM_(w) distribution results in more urethane crosslinks between mid M_(w)fractions when the PGS resin is reacted with isocyanate to form PGSU.Having less low M_(w) fractions available to participate in crosslinkingleads to less chance the isocyanate will react with those small fugitivepolymer chains, resulting in a PGSU crosslink network structure,three-dimensional conformation, and mesh size that display greaterimpermeability when the water-mediated process is used to synthesize PGSresin. Conversely, a non-water-mediated synthesized resin results in aPGSU crosslink network with higher permeability and less controlled drugrelease.

Example 2

Sixteen samples of PGSU films were formed by reacting each of Resin 1through Resin 8 by combining and mixing each PGS resin with HDI at twodifferent PGS:HDI mass ratios, 2.5:1 and 3.5:1, during film fabrication.

The crosslinking of each PGSU film was estimated by FTIR spectroscopyand a multiple linear regression (MLR) model that used the integratedarea of peaks highly correlated with crosslinking density. The resultingestimated crosslinking is shown in FIG. 4 as a PGS:HDI mass ratio. ThePGS:HDI mass ratio is related to the crosslinking density, as shown inExample 5. PGS:HDI mass ratio can be converted to NCO:OH stoichiometricratio using the hydroxyl value of the PGS resin and the equivalentweight of OH and equivalent weight of NCO. For reference, 3.5:1 PGS:HDImass ratio films are less crosslinked than 2.5:1 PGS:HDI mass ratiofilms. FIG. 4 shows that different resins demonstrate differentcrosslinking behaviors, in some cases having lower crosslinking thanwould be expected if the PGS resin were Regenerez® RG-300 PGS resin,which the MLR model is based on and was trained with. For example, beingestimated at 3:1 when the film was mixed at 2.5:1 is alower-than-expected crosslinking. In some cases, PGS resins did notexhibit an increase in estimated PGS:HDI mass ratio despite an increasein the actual mass ratio from 3.5:1 to 2.5:1. In other cases, PGS resinsexhibited a more dramatic increase in crosslinking between the massratios 3.5:1 and 2.5:1 than would be expected if using Regenerez® RG-300PGS resin.

FIG. 5 shows crosslinking density, as determined by Flory-Rehner swelltesting, of the sixteen PGSU films. Crosslinking in FIG. 5 is shown asmoles per liter and describes the ability of a polymer network to swell.For reference, 3 mol/L films are more crosslinked than 2 mol/L films.

Example 3

The sixteen samples of PGSU films were tested to determine elasticmodulus, with the results being shown in FIG. 6, and strain at break,with the results being shown in FIG. 7, as determined by tensiletesting. As shown in FIG. 7, PGSU films did not break in some cases suchthat no strain at break data could be collected. In these cases,increased PGSU crosslinking led to a tougher polymer that did not break,as opposed to a more brittle polymer behavior that might have beenexpected.

Example 4

Extractables from above the sixteen samples of PGSU films were collectedand tested for weight-average molecular weight and polydispersity index,as determined by GPC, with the results being shown in FIG. 8. The M_(w)species and PDI of the extractables was fairly similar across allsamples, but the extractable M_(w) tended to be slightly higher forintermediate PGS resin M_(w) values. The proportion of extractablespecies varied across the different films' extractables, where filmsgenerated from water-mediated PGS resins tended to demonstrate less lowM_(w) fractions compared to films made from non-water-mediated PGSresins. The extracted mass and percentage of the mass extracted relativeto the initial sample mass were also determined, with the results beingshown in FIG. 9. The mass percentage of the extractables was morevariable with PGS resin M_(w) variation for the non-water-mediated PGSUsamples.

Example 5

Sixteen samples of PGSU films were formed as in Example 4, except in thepresence of caffeine to form 60% w/w caffeine-loaded PGSU film samples.The sixteen samples of PGSU films were tested to determine waterpermeability and percolation, which directly relate to burst release anddiffusion behaviors during drug release, with the results being shown inFIG. 10, FIG. 11, and Table 2. A modified water vapor transmissionmethod from ASTM E96 was used, where a PGSU film barrier was placed overthe top of a water-filled cup and inverted, so the water made directcontact with and could permeate through the PGSU film. High (>60% w/w)drug loadings of caffeine within PGSU films may exhibit some degree ofpercolation, due to high interconnectivity of caffeine drug particlesspaced within the polymer matrix, creating interconnected channels andallowing for water infiltration. This was grossly visualized by theamount of caffeine precipitation the backside of the film. If water canpermeate and percolate through the matrix, it will solubilize caffeineupon contact and carry the caffeine molecules along with it, until thewater passes through the full film thickness and evaporates, leavingbehind caffeine crystals. FIG. 10 images demonstrate that after twoweeks 60% w/w loaded PGSU films experienced different degrees ofpermeation and percolation based on the resin and crosslinking densitythat was used. This can also be visualized more thoroughly using SEM, inFIG. 11, where cross-sections of films illustrate how far water was ableto permeate and percolate in after two weeks, leaving behind voids wherecaffeine particles were solubilized and carried away. Arrows indicatedirection of water infiltration. Water loss from the cup reservoirthrough the film over two weeks was quantified, with the results beingshown below in Table 2.

TABLE 2 Water Loss through PGSU Films after 14 Days Loading PGS:HDIInitial Water Final Water Total Loss Resin (% w/w) Ratio (mL) (mL) (%) 160 2.5:1 50 43 14 3.5:1 50 18.5 63 2 60 2.5:1 50 26 48 3.5:1 50 10.5 793 60 2.5:1 50 48 4 3.5:1 50 48 4 4 60 2.5:1 50 48 4 3.5:1 50 35 30 5 602.5:1 50 11 78 3.5:1 50 N/A N/A 6 60 2.5:1 50 45 10 3.5:1 50 13 74 7 602.5:1 50 44 12 3.5:1 50 15 70 8 60 2.5:1 50 47 6 3.5:1 50 46 8

The data in Table 2 demonstrates a good correlation with the gross andSEM images of FIG. 10 and FIG. 11, respectively. Increasing PGSUcrosslinking density from 3.5:1 to 2.5:1 reduced permeation andpercolation of water through caffeine-loaded polymer films, for most,but not all, of the PGSU films made from different PGS resins.

Example 5

Unloaded PGSU films were prepared by using a 60% w/w PGS solution in 1:1(w/w) of acetone:propyl acetate. Regenerez® RG-300 PGS resin was used inthis Example and all of the following Examples. Tin catalyst was addedfollowed by HDI. Films were poured into molds and allowed to crosslinkat room temperature for 24 hours, followed by a drying period at 40° C.for 6 days. The PGSU samples of different PGS:HDI mass ratios forunloaded (neat) formulations were synthesized and crosslink density wasthen measured. PGS:HDI mass ratios of 2:1 have higher crosslinking thanratios of 4:1 due to increased isocyanate in the formulation, but PGSUcrosslinking does not follow a linear relationship with PGS:HDI massratio, as shown in FIG. 12.

FIG. 13 shows how PGS:HDI mass ratio relates to isocyanate-to-hydroxylstoichiometric ratio, for a PGS resin with a hydroxyl number between 160and 240. For a given PGS:HDI mass ratio, a range ofisocyanate-to-hydroxyl stoichiometric ratios could exist, depending onthe hydroxyl number of the PGS resin. Gray data points demonstrate thisrelationship for a PGS resin with a hydroxyl number of 160, while blackdata points demonstrate this relationship for a PGS resin with ahydroxyl number of 240.

Swellability in saline solution of unloaded (neat) PGSU films having aPGS:HDI mass ratio 3.6:1 at 23° C. and 37° C., as measured by weightincrease, remains below about 2.5% w/w across 14 days as shown in FIG.14.

For a PGS resin with a hydroxyl number between 160 and 240, a PGS:HDImass ratio of 3.6:1 results in an isocyanate-to-hydroxyl stoichiometricratio between 1:0.86 and 1:1.3.

Example 7

PGSU samples (50) manufactured with a PGS:HDI mass ratio of 8.3:1 wereinitially clear, but became cloudy by three months after manufacture.The PGSU samples (50) remained cloudy through eight months aftermanufacture, as shown in FIG. 15. PGSU samples (60) manufactured with aPGS:HDI mass ratio of 3.6:1 were initially clear and remained clearthrough three months after manufacture. The PGSU samples (60) remainedclear through eight months after manufacture, as shown in FIG. 15.

The lack of clarity seen in the 8.3:1 PGS:HDI mass ratio polymer may bean indicator of instability and thus poor shelf life. The instabilitymay be in the form of polymer chain reorientation, migration, orblooming. Clouding, hazing, and blooming may impact product quality,shelf life, and controlled release behavior.

For a PGS resin with a hydroxyl number between 160 and 240, a PGS:HDImass ratio of 3.6:1 results in an isocyanate-to-hydroxyl stoichiometricratio between 1:0.86 and 1:1.3, while a PGS:HDI mass ratio of 8.3:1results in an isocyanate-to-hydroxyl stoichiometric ratio between 1:2 to1:3. Accordingly, this data shows that polymer clouding occurs atisocyanate-to-hydroxyl stoichiometric ratios below 1:2, such as, forexample, 1:3 or 1:4.

Example 8

Seven samples of API-loaded PGSU were formed with caffeine as the API tomeasure drug release from PGSU during in vivo pharmacokinetic testingusing a rat pre-clinical model with dorsal subcutaneous implantation.The PGSU was formed from PGS resin having a weight-average molecularweight of about 18,000 Da and a polydispersity index of about 9. Asshown in Table 3 below, six of the samples had a low crosslinkingdensity in the range of 0.51 to 0.89 mol/L and either a lower initialloadings of caffeine in the range of 18.2% to 20.9% w/w or a higherinitial loading of caffeine in the range of 24.8% to 25.3% w/w. SampleR7 had a high crosslinking density of 2.75 mol/L and an intermediateloading of caffeine.

Each sample was implanted by dorsal subcutaneous implantation in aWistar Han rat model, and caffeine release from each sample in vivo wasmonitored over about 90 days. FIG. 16 shows the caffeine concentrationmeasured in plasma, indicating sustained release of caffeine over the3-month time period for most samples. The high crosslinking sample had asignificantly slower release rate than the low crosslinking samples. Theresidual loading was measured at the end of the study, with the measuredvalues being shown in Table 3.

TABLE 3 PGSU-caffeine in vivo Sample Data Crosslinking Density InitialLoading Residual Loading Sample (mol/L) (% w/w) (% w/w) R1 0.85 20.9 0.7R2 0.86 18.2 0.0 R3 0.89 18.3 N/A R4 0.51 19.6 N/A R5 0.65 24.8 0.0 R60.64 25.3 0.0 R7 2.75 23.7 18.9 

Release rate was near zero-order across different loadings and differentcrosslinking levels. Burst release was particularly minimal in highlycrosslinked PGSU rods, with only a 4-fold difference in concentrationbetween C_(max) and C_(steady) for R7. PGSU rods were fabricated withcaffeine loading range from about 15% to 25% w/w. Based on residualcaffeine loading in explanted rods, only about 20% of the caffeinepayload was released over 3 months for the highly crosslinked PGSU rodin R, and it can be extrapolated that the implant may have continuedreleasing caffeine for 9 additional months, totaling 12 months ofrelease.

Example 9

Eight samples of API-loaded PGSU rods were formed with caffeine as theAPI at loading range from about 15% to about 25% w/w. Samples werestored either three months under accelerated aging conditions or sixmonths under real time aging conditions. As shown in Table 4 below, twoof the real-time aged samples had low initial loadings of caffeine, twoof the real-time aged samples had high initial loadings of caffeine, twoof the accelerated aged samples had low initial loadings of caffeine,and two of the accelerated aged samples had high initial loadings ofcaffeine. Most of the samples had low crosslinking levels, but F4 and F8had high crosslinking levels.

TABLE 4 PGSU-caffeine in vitro Sample Data Sample Shelf Life StorageInitial Loading (% w/w) F1 6 months, real time aging 14.6 F2 6 months,real time aging 14.9 F3 6 months, real time aging 24.8 F4 6 months, realtime aging 19.3 F5 3 months, accelerated aging 12.1 F6 3 months,accelerated aging 15.7 F7 3 months, accelerated aging 24.6 F8 3 months,accelerated aging 20.5

Each sample was placed in a flow-through cell USP IV apparatus with flowof 0.1 M phosphate-buffered saline (PBS) at a pH of 7.4 at 37° C. and aflow rate of 8 mL/min, and the cumulative release of caffeine from eachsample in vitro was monitored over about 55 days. FIG. 17 shows thecumulative amount of caffeine in the PBS, indicating sustained releaseof caffeine over the 2-month time period for all samples. The highcrosslinking samples had significantly slower release rates.

Example 10

The percentage of cumulative release of caffeine was plotted for boththe in vivo and the in vitro experiments of Examples 8 and 9. Theresults are shown in FIG. 18. Both the in vivo and the in vitroexperiments had similar release curves for the low crosslinking samples,regardless of the API loading percentage.

To determine the correlation between the in vivo and the in vitroresults, pairs of in vivo and in vitro samples with similar relative APIloadings and similar relative crosslinking levels were matched up andeach data point in FIG. 8 represents the fractional area under the curve(AUC) for the in vivo sample and the cumulative release for the in vitrosample at the same time from the start of each experiment. As shown bythe line fits in FIG. 19, correlation shows agreement between methodsand grouping of higher crosslinked PGSU compared to lower crosslinkedPGSU. Different drug loadings did not dramatically affect in vivo-invitro correlation linearity or slope.

The release rates for the seven samples of Example 8 and the eightsamples of Example 9 were calculated based on the release data. FIG. 20shows the release rate plotted as a function of the initial caffeineloading indicating a zero-order or near zero-order release ratesubstantially independent of API loading across the tested API loadings.During both in vitro and in vivo caffeine release from PGSU, the rateconstant remains nearly the same across drug loadings and appears to beindependent of drug loading. PGSU's surface erosion properties allow forthis, compared to bulk-eroding or non-degradable polymers where the rateconstant dramatically increases as drug loading is increased. Highercrosslinked PGSU can be grouped separately from lower crosslinked PGSUand exhibited a much lower rate constant of about 2 day^(1/2), whilelower crosslinked PGSU exhibited a rate constant of about 8 to about 12day^(1/2). The lower the rate constant, the longer a drug-releasingimplant can provide therapy. Achieving long-lasting implants are highloadings has been prohibitive for bulk-eroding and non-degradablepolymers, but surface-eroding PGSU overcomes this limitation.

Caffeine-loaded PGSU demonstrates diffusion-driven drug release whenPGSU crosslinking is low, but at high PGSU crosslinking, diffusion iscurtailed and drug release is driven truly by surface erosion.Cross-sectional images shown in FIG. 21A illustrate rods before andafter implantation in rats, and cross-sectional images in FIG. 21Billustrate rods before and after dissolution testing. In cases wheredrug diffused out of the matrix, voids were left behind where pockets ofcaffeine used to be present, in lower crosslinked PGSU. In highercrosslinked PGSU, no voids were present, and water or bodily fluids werenot able to penetrate into the matrix and cause drug diffusion back outof the matrix. By increasing PGSU crosslinking, diffusion and burstrelease can be minimized or eliminated entirely.

Example 11

Loaded PGSU films were prepared by using a 60% w/w PGS solution in 1:1(w/w) of acetone:propyl acetate. Tin catalyst was added, followed bycaffeine as a model compound, followed by HDI. Films were poured intomolds and allowed to crosslink at room temperature for 24 hours,followed by a drying period at 40° C. for 6 days. Four caffeine-loadedPGSU films were formed and tested for water permeability using amodified water vapor transmission method from ASTM E96, where a filmbarrier was placed over the top of a water-filled cup and inverted, sothe water made direct contact with and could permeate through the PGSUfilm. Two films had 40% w/w caffeine loading and the other two had 60%w/w loading. One each of the 40% and 60% loadings was formed with a3.5:1 PGS:HDI mass ratio and the others were formed with a 2:1 PGS:HDImass ratio. Higher drug loadings of caffeine within PGSU films led toincreased percolation, due to increased interconnectivity of caffeinedrug particles spaced within the polymer matrix, creating interconnectedchannels and allowing for easier water infiltration. This can be grosslyvisualized by the amount of caffeine precipitation the backside of thefilm. If water can permeate and percolate through the matrix, it willsolubilize caffeine upon contact and carry the caffeine molecules alongwith it, until the water passes through the full film thickness andevaporates, leaving behind caffeine crystals. FIG. 22 shows that 60% w/wloaded PGSU films experienced greater permeation and percolation than40% w/w loaded films. FIG. 22 also includes SEM images of cross-sectionsof films that illustrate how far water was able to permeate andpercolate in, leaving behind voids where caffeine particles weresolubilized and carried away. Arrows indicate direction of waterinfiltration. Increasing PGSU crosslink density from 3.5:1 to 2:1reduced permeation and percolation of water through caffeine-loadedpolymer films, both for 40% w/w and 60% w/w loaded films.

For a PGS resin with a hydroxyl number between 160 and 240, a PGS:HDImass ratio of 2:1 results in an isocyanate-to-hydroxyl stoichiometricratio between 1:0.48 and 1:0.72, 2.5:1 results in anisocyanate-to-hydroxyl stoichiometric ratio between 1:0.6 and 1:0.9, 3:1results in an isocyanate-to-hydroxyl stoichiometric ratio between 1:0.72and 1:1.08, and 3.5:1 results in an isocyanate-to-hydroxylstoichiometric ratio between 1:0.84 and 1:1.26.

Example 12

PGSU rods were loaded with different types of model drug substancesincluding barium sulfate (20% w/w), USP grade barium sulfate (20% w/w),and caffeine (20% and 30% w/w), but still exhibited a high flexibilityand tight bend radius of about 1 to 2 mm when folded 180° comparable toneat (unloaded) PGSU rods.

Example 13

Unloaded PGSU sheets with PGS:HDI mass ratios of 2:1, 2.5:1, 3:1, 3.5:1and 4:1 were interrogated using FTIR to assess the spatial homogeneityof crosslinking density and relatedly uniformity of mixing. PGSU filmswere prepared by using a 60% w/w PGS solution in 1:1 (w/w) ofacetone:propyl acetate. Tin catalyst was added followed by HDI. Highshear mixing techniques were employed at component addition steps. Filmswere poured into molds and allowed to crosslink at room temperature for24 hours, followed by a drying period at 40 C for 6 days. No differencesin FTIR peaks associated with urethane or ester crosslinking bonds wereobserved across five distinct spatial locations on PGSU films, as shownin FIG. 23 for 2:1 PGS:HDI mass ratio films in the region between 1800and 800 cm⁻¹. Additionally, no differences in spectra were observed inthe hydroxyl region between 3500 and 3100 cm⁻¹. The region between 1475and 1400 cm⁻¹ are C—H₂ alkane bends and C—H alkene in-plane bends thatare not associated with urethane bonds in PGSU crosslinking. Further, nodifferences in any FTIR peaks were observed between unsterilized andgamma-irradiated sterile PGSU sheets. However, film fabrication methodsthat did not incorporate high shear mixing techniques but otherwise wereidentical failed to achieve mixing uniformity and spatial homogeneity ofcrosslinking density, as evidenced by highly variable FTIR peaksassociated with urethane and ester crosslinking bonds, as shown in FIG.24 for 2:1 PGS:HDI mass ratio films in the region between 1800 and 800cm⁻¹. It becomes especially challenging to achieve good mixing at highcrosslinking where large volumes of isocyanate are used, such as 2:1PGS:HDI mass ratio, due to miscibility and viscosity issues. FIG. 23 andFIG. 24 show the importance of high shear mixing, particularly at 2:1PGS:HDI mass ratio.

For a PGS resin with a hydroxyl number between 160 and 240, a PGS:HDImass ratio of 2:1 results in an isocyanate-to-hydroxyl stoichiometricratio between 1:0.48 and 1:0.72, 2.5:1 results in anisocyanate-to-hydroxyl stoichiometric ratio between 1:0.6 and 1:0.9, 3:1results in an isocyanate-to-hydroxyl stoichiometric ratio between 1:0.72and 1:1.08, 3.5:1 results in an isocyanate-to-hydroxyl stoichiometricratio between 1:0.84 and 1:1.26, and 4:1 results in anisocyanate-to-hydroxyl stoichiometric ratio between 1:0.96 and 1:1.44.

Example 14

The neat (unloaded) PGSU and (loaded) PGSU with caffeine-loading ofExample 8 were observed to demonstrate biocompatibility after 3 monthsof implantation in rats, with minimal fibroplasia, no fibrousencapsulation, and no lymphocyte or macrophage infiltration uponhistological inspection, indicating no adverse response to the material,its leachables, or its degradation byproducts as shown in FIG. 25.Additionally, following ISO 10993 testing for cytotoxicity, acutesystemic toxicity, irritation, and implantation, unloaded PGSU sheetswith a 3.6:1 PGS:HDI mass ratio passed all biocompatibility tests withscores of 0 across all samples and all animals, indicating no adverseresponse to the material or its extractables and leachables. PGS-basedbiomaterials have breakdown products less acidic than other polyesterssuch as PLGA, PGA, or PLA, which reduces the inflammatory response,toxicity, delayed healing, and negative impact on cells resulting fromacidic pH. Further, more highly crosslinked PGSU may incite less acuteinflammation, chronic inflammation, and fibrosis due to fewer exposedchemical functional groups at the cell-interfacing surface that mayaggravate or activate immune cells.

For a PGS resin with a hydroxyl number between 160 and 240, a PGS:HDImass ratio of 3.6:1 results in an isocyanate-to-hydroxyl stoichiometricratio between 1:0.86 and 1:1.3.

Example 15

Neat (unloaded) PGSU and (loaded) PGSU with caffeine-loading, from thesame batch of rod samples referenced in Example 8, were mechanicallytested before and after gamma irradiation using 3-point bending andaxial compression, as shown in FIG. 26 and FIG. 27, respectively, anddifferences between high crosslinking and low crosslinking wereobserved. Unloaded PGSU sheets with a 3.6:1 PGS:HDI mass ratio weremechanically tested using axial tension, as shown in FIG. 28. Nosignificant differences were detected between unsterilized andgamma-irradiated sterile PGSU, either for rods or sheets.

For a PGS resin with a hydroxyl number between 160 and 240, a PGS:HDImass ratio of 3.6:1 results in an isocyanate-to-hydroxyl stoichiometricratio between 1:0.86 and 1:1.3.

Example 16

Solvent-less PGSU rod implants were created using a high shear mixingtechnique followed by a dual-barrel syringe extrusion technique,formulated with 40% w/w and 60% w/w caffeine and 2:1 PGS:HDI mass ratio.Temperatures were maintained below 40° C. throughout the process.

FIG. 29A and FIG. 29B illustrate via SEM uniform caffeine distributionthrough the cross-section of PGSU rods formed using the solvent-lessmethod at less than 40° C. FIG. 29A shows 40% w/w caffeine-loaded PGSUand FIG. 29B shows 60% w/w caffeine-loaded PGSU.

FIG. 30 and FIG. 31 illustrate the uniformity of rods created across abatch using the dual-barrel syringe method, demonstrating successfulmixing was achieved, even at high crosslinking and high loading wherelarge amounts of HDI and API required homogeneous incorporation.Uniformity across the batch was assessed according to crosslink density,caffeine content, and elastic modulus. FIG. 30 shows 40% w/wcaffeine-loaded PGSU, and FIG. 31 is 60% w/w caffeine-loaded PGSU.Crosslinking and % caffeine were determined using a thermogravimetricanalysis (TGA) method quantifying the mass loss associated with urethanecrosslink content and caffeine content, respectively, and are displayedon the left-hand y-axis. Elastic modulus was determined using axialcompression and is displayed on the right-hand y-axis.

For a PGS resin with a hydroxyl number between 160 and 240, a PGS:HDImass ratio of 2:1 results in an isocyanate-to-hydroxyl stoichiometricratio between 1:0.48 and 1:0.72.

All references cited herein are hereby incorporated by reference intheir entirety.

While the foregoing specification illustrates and describes exemplaryembodiments, it will be understood by those skilled in the art thatvarious changes may be made and equivalents may be substituted forelements thereof without departing from the scope of the invention. Inaddition, many modifications may be made to adapt a particular situationor material to the teachings of the invention without departing from theessential scope thereof. Therefore, it is intended that the inventionnot be limited to the particular embodiment disclosed as the best modecontemplated for carrying out this invention, but that the inventionwill include all embodiments falling within the scope of the appendedclaims.

What is claimed is:
 1. A process of forming an implantable productcomprising poly(glycerol sebacate) urethane loaded with an activepharmaceutical ingredient, the process comprising: homogeneously mixinga flowable poly(glycerol sebacate) resin with the active pharmaceuticalingredient and a catalyst to form a resin blend; selecting an amount ofisocyanate such that an isocyanate-to-hydroxyl stoichiometric ratio isin the range of 1:0.25 to 1:1.25; homogeneously combining the resinblend with the isocyanate to form a reaction mixture; and injecting thereaction mixture to form the poly(glycerol sebacate) urethane loadedwith the active pharmaceutical ingredient.
 2. The process of claim 1,wherein the active pharmaceutical product is at least 10% w/w of theimplantable product.
 3. The process of claim 1, wherein the weightaverage molecular weight of the flowable poly(glycerol sebacate) resinis greater than 10,000 Da.
 4. The process of claim 1, wherein thehomogeneous combining comprises shear mixing.
 5. The process of claim 1,wherein the injecting comprises reaction injection molding.
 6. Theprocess of claim 1, wherein the injecting further comprises removinggenerated gasses, entrained gasses, entrapped gasses, or combinationsthereof.
 7. The process of claim 6, wherein the removing occurs undervacuum.
 8. The process of claim 6, wherein the removing occurs undersonication.
 9. The process of claim 1, wherein the process occurs at atemperature of 60° C. or less.
 10. The process of claim 1, wherein thehomogeneous mixing occurs in the absence of a solvent.
 11. The processof claim 1, wherein the flowable poly(glycerol sebacate) resin is freeof a solvent.
 12. The process of claim 1, wherein the resin blendincludes no more than 50% w/w of a solvent.
 13. The process of claim 12further comprising evaporating the solvent from the poly(glycerolsebacate) urethane loaded with the active pharmaceutical ingredient at atemperature of up to 40° C. for up to 6 days.
 14. The process of claim1, wherein the injecting comprises injecting the reaction mixture into amold.
 15. The process of claim 1 further comprising crosslinking thepoly(glycerol sebacate) urethane loaded with the active pharmaceuticalingredient for up to 24 hours at up to 40° C. to form the implantableproduct.
 16. The process of claim 1, wherein the injecting the reactionmixture comprises an additive manufacturing process to form theimplantable product.
 17. The process of claim 1, wherein the catalyst isselected from the group consisting of a potassium catalyst, potassiumtartrate, and potassium citrate.
 18. An implantable product formed bythe process of claim
 1. 19. An implantable product comprising apoly(glycerol sebacate) urethane loaded with an active pharmaceuticalingredient, wherein the implantable product releases the activepharmaceutical ingredient by surface degradation of the poly(glycerolsebacate) urethane at a predetermined release rate for at least threemonths under physiological conditions.
 20. The implantable product ofclaim 19, wherein the poly(glycerol sebacate) urethane is loaded with atleast 10% w/w of the active pharmaceutical ingredient.
 21. Theimplantable product of claim 19, wherein the poly(glycerol sebacate)urethane is loaded with at least 40% w/w of the active pharmaceuticalingredient.
 22. The implantable product of claim 19, wherein theimplantable product comprises more than one compartment.
 23. Theimplantable product of claim 22, wherein the implantable productcomprises a second active pharmaceutical ingredient.
 24. The implantableproduct of claim 19, wherein the poly(glycerol sebacate) urethane loadedwith the active pharmaceutical ingredient forms a plurality of fibers.25. An implantable product comprising a poly(glycerol sebacate) urethaneloaded with an active pharmaceutical ingredient, wherein thepoly(glycerol sebacate) urethane is formed from a poly(glycerolsebacate) reacted with an isocyanate at an isocyanate-to-hydroxylstoichiometric ratio is in the range of 1:0.25 to 1:1.25.
 26. Theimplantable product of claim 25, wherein the poly(glycerol sebacate)urethane is formed from a poly(glycerol sebacate) resin having amolecular weight greater than 10,000 Da.
 27. The implantable product ofclaim 25, wherein the poly(glycerol sebacate) urethane is formed from apoly(glycerol sebacate) resin having a polydispersity index less than12.
 28. The implantable product of claim 25, wherein the poly(glycerolsebacate) urethane is formed from a poly(glycerol sebacate) resin havinga glycerol-to-sebacic acid stoichiometric ratio of between 1:0.5 and1:1.5.
 29. The implantable product of claim 25, wherein the isocyanateis a blocked isocyanate.
 30. The implantable product of claim 25,wherein the active pharmaceutical ingredient is at least 40% w/w of theimplantable product.